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1
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Qian Y, Liu C, Zeng X, Li LC. RNAa: Mechanisms, therapeutic potential, and clinical progress. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102494. [PMID: 40125270 PMCID: PMC11930103 DOI: 10.1016/j.omtn.2025.102494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
RNA activation (RNAa), a gene regulatory mechanism mediated by small activating RNAs (saRNAs) and microRNAs (miRNAs), has significant implications for therapeutic applications. Unlike small interfering RNA (siRNA), which is known for gene silencing in RNA interference (RNAi), synthetic saRNAs can stably upregulate target gene expression at the transcriptional level through the assembly of the RNA-induced transcriptional activation (RITA) complex. Moreover, the dual functionality of endogenous miRNAs in RNAa (hereafter referred to as mi-RNAa) reveals their complex role in cellular processes and disease pathology. Emerging studies suggest saRNAs' potential as a novel therapeutic modality for diseases such as metabolic disorders, hearing loss, tumors, and Alzheimer's. Notably, MTL-CEBPA, the first saRNA drug candidate, shows promise in hepatocellular carcinoma treatment, while RAG-01 is being explored for non-muscle-invasive bladder cancer, highlighting clinical advancements in RNAa. This review synthesizes our current understanding of the mechanisms of RNAa and highlights recent advancements in the study of mi-RNAa and the therapeutic development of saRNAs.
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Affiliation(s)
- Yukang Qian
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
| | - Cody Liu
- Univeristy of California, Davis, Davis, CA 95616, USA
| | - Xuhui Zeng
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
| | - Long-Cheng Li
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu 226019, China
- Ractigen Therapeutics, Nantong, Jiangsu 226400, China
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2
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Bakrania A, Mo Y, Zheng G, Bhat M. RNA nanomedicine in liver diseases. Hepatology 2025; 81:1847-1877. [PMID: 37725757 PMCID: PMC12077345 DOI: 10.1097/hep.0000000000000606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 09/08/2023] [Indexed: 09/21/2023]
Abstract
The remarkable impact of RNA nanomedicine during the COVID-19 pandemic has demonstrated the expansive therapeutic potential of this field in diverse disease contexts. In recent years, RNA nanomedicine targeting the liver has been paradigm-shifting in the management of metabolic diseases such as hyperoxaluria and amyloidosis. RNA nanomedicine has significant potential in the management of liver diseases, where optimal management would benefit from targeted delivery, doses titrated to liver metabolism, and personalized therapy based on the specific site of interest. In this review, we discuss in-depth the different types of RNA and nanocarriers used for liver targeting along with their specific applications in metabolic dysfunction-associated steatotic liver disease, liver fibrosis, and liver cancers. We further highlight the strategies for cell-specific delivery and future perspectives in this field of research with the emergence of small activating RNA, circular RNA, and RNA base editing approaches.
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Affiliation(s)
- Anita Bakrania
- Department of Medicine, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Department of Medicine, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Yulin Mo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Department of Medicine, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Department of Medicine, Ajmera Transplant Program, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, Division of Gastroenterology, University Health Network and University of Toronto, Toronto, Ontario, Canada
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3
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Kim SI, Lyu H, Pujara DS, Bordiya Y, Bhatt PS, Mayorga J, Zogli PK, Kundu P, Chung H, Yan X, Zhang X, Kim J, Louis J, Yu Q, Kang HG. A nuclear tRNA-derived fragment triggers immunity in Arabidopsis. Commun Biol 2025; 8:533. [PMID: 40169869 PMCID: PMC11962134 DOI: 10.1038/s42003-025-07737-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 02/13/2025] [Indexed: 04/03/2025] Open
Abstract
In Arabidopsis, effector-triggered immunity (ETI) against avirulent Pseudomonas syringae pv. tomato (Pst) correlates with the rapid, Dicer-Like 1 (DCL1)-dependent nuclear accumulation of a 31-nt 5'-tRNA fragment derived from Asp-tRNA (tRF31Asp2). Several tRFs, including tRF31Asp2, are induced at early stages of infection and associate with AGO2 in the nucleus. Infiltrating Arabidopsis leaves with synthetic tRF31Asp2 induces over 500 defense-associated genes, conferring immunity against virulent and avirulent Pst as well as aphids, while tRF31Asp2 depletion compromises resistance to avirulent Pst. The biological activity of tRF31Asp2 requires its 5' sequence and predicted stem-loop structure, and its loading into AGO2 or related clade members may contribute to activating defense responses. Chromatin affinity precipitation-sequencing revealed that tRF31Asp2 binds specific sequences in defense genes and the Gypsy superfamily of LTR retrotransposons, particularly at their primer binding sites (PBS). tRF31Asp2 binding appears to modulate transcriptional reprogramming, inducing neighboring tRF-responsive defense genes while suppressing active retrotransposons. Since Gypsy retrotransposon proliferation is primed by tRNA binding at PBS, tRF31Asp2 may exploit a similar mechanism to coordinate defense responses. Together, these findings reveal a role for DCL1 and tRF31Asp2 in regulating plant immunity and transcriptional dynamics at defense-associated loci and retrotransposons.
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Affiliation(s)
- Sung-Il Kim
- Department of Biology, Texas State University, San Marcos, USA
- Department of Molecular Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Haomin Lyu
- Texas A&M AgriLife Research, Texas A&M University System, Dallas, TX, USA
- Huazhi Biotechnology, Changsha, Hunan, China
| | - Dinesh S Pujara
- Department of Biology, Texas State University, San Marcos, USA
- School of Integrated Plant Science, Cornell University, Ithaca, NY, USA
| | - Yogendra Bordiya
- Department of Biology, Texas State University, San Marcos, USA
- Biosciences Division, Thermo Fisher Scientific, Austin, TX, USA
| | - Padam S Bhatt
- Department of Biology, Texas State University, San Marcos, USA
| | - José Mayorga
- Department of Biology, Texas State University, San Marcos, USA
| | - Prince K Zogli
- Department of Entomology & Department of Biochemistry, University of Nebraska, Lincoln, NE, USA
- GALY.CO, Boston, MA, USA
| | - Pritha Kundu
- Department of Entomology & Department of Biochemistry, University of Nebraska, Lincoln, NE, USA
| | - Haewon Chung
- Department of Molecular Biosciences, University of Texas, Austin, TX, USA
- Synthetic biology, Asimov, Boston, MA, USA
| | - Xingxing Yan
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, USA
| | - Xiuren Zhang
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX, USA
| | - Jonghwan Kim
- Department of Molecular Biosciences, University of Texas, Austin, TX, USA
| | - Joe Louis
- Department of Entomology & Department of Biochemistry, University of Nebraska, Lincoln, NE, USA
| | - Qingyi Yu
- Daniel K. Inouye U.S. Pacific Basin Agricultural Research Center, USDA Agricultural Research Service, Hilo, HI, USA
| | - Hong-Gu Kang
- Department of Biology, Texas State University, San Marcos, USA.
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4
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Zhang X, Deng Z, Xu X, Zhu J, Huang Z, Ye Y, Liu J, Luo D, Liu J, Yan M, Song Y. Tetrahedral Framework Nucleic Acid-Based Delivery of DJ-1-saRNA Prevent Retinal Ischaemia-Reperfusion Injury via Inhibiting Ferroptosis. Cell Prolif 2025:e13820. [PMID: 39980149 DOI: 10.1111/cpr.13820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/09/2025] [Accepted: 01/17/2025] [Indexed: 02/22/2025] Open
Abstract
Retinal ischaemia/reperfusion injury (RI/RI) is the primary pathophysiological mechanism underlying retinal ischaemic diseases, potentially resulting in significant and irreversible visual impairment. Currently, there are no effective treatments available for RI/RI, and oxidative stress is a critical factor that contributes to the associated damage. DJ-1, an important endogenous antioxidant, has been proposed as a promising therapeutic agent for RI/RI owing to its potential for overexpression. In this study, tetrahedral frame nucleic acids (tFNAs) were utilised as an effective delivery vehicle for DJ-1 small activating RNA (saRNA), resulting in the synthesis of a novel nanocomposite (tFNAs-DJ-1-saRNA). In vitro experiments demonstrated that tFNAs effectively delivered DJ-1-saRNA to R28 cells, thus exerting a repair effect on oxidative stress injury. In vivo investigations revealed that the intravitreal injection of tFNAs-DJ-1-saRNA facilitated retinal DJ-1 gene expression and mitigated retinal atrophy induced by RI/RI. Mechanistically, tFNAs-DJ-1-saRNA activated the xCT/GPX4 pathway, thereby inhibiting ferroptosis, reducing ganglion cell damage and protecting the retinal tissue. In conclusion, this study demonstrated that the tFNAs-DJ-1-saRNA complex can ameliorate RI/RI by inhibiting ferroptosis, suggesting its potential as a novel agent for the treatment of retinal ischaemic diseases.
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Affiliation(s)
- Xianggui Zhang
- The First School of Clinical Medical, Southern Medical University, Guangzhou, China
| | - Zhende Deng
- The First School of Clinical Medical, Southern Medical University, Guangzhou, China
| | - Xiaoxiao Xu
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingyi Zhu
- Department of Ophthalmology, General Hospital of Central Theater Command, Wuhan, China
| | - Zhen Huang
- Department of Ophthalmology, General Hospital of Central Theater Command, Wuhan, China
| | - Ya Ye
- Department of Ophthalmology, General Hospital of Central Theater Command, Wuhan, China
| | - Jingying Liu
- Department of Ophthalmology, General Hospital of Central Theater Command, Wuhan, China
| | - Delun Luo
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinnan Liu
- Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ming Yan
- Department of Ophthalmology, General Hospital of Central Theater Command, Wuhan, China
| | - Yanping Song
- The First School of Clinical Medical, Southern Medical University, Guangzhou, China
- Department of Ophthalmology, General Hospital of Central Theater Command, Wuhan, China
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5
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Parr MK, Keiler AM. Oligonucleotide therapeutics in sports? An antidoping perspective. Arch Pharm (Weinheim) 2025; 358:e2400404. [PMID: 39449227 PMCID: PMC11704058 DOI: 10.1002/ardp.202400404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/26/2024] [Accepted: 09/30/2024] [Indexed: 10/26/2024]
Abstract
Within the last two decades, the European Medicines Agency and the US Food and Drug Administration have approved several gene therapies. One category is oligonucleotide therapeutics, which allow for the regulation of the expression of target genes. Besides already approved therapeutics, there are several preclinical and clinical trials ongoing. The World Anti-Doping Agency prohibits the use of "nucleic acids or nucleic acid analogs that may alter genome sequences and/or alter gene expression by any mechanism" as a nonspecified method at all times. Hence, the administration of nucleic acids or analogs by athletes would cause an Anti-Doping Rule Violation. Herein, we discuss types of oligonucleotide therapeutics, their potential to be misused in sports, and considerations to sample preparation and mass spectrometric approaches with regard to antidoping analysis.
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Affiliation(s)
- Maria K. Parr
- Institute of Pharmacy, Pharmaceutical and Medicinal ChemistryFreie Universität BerlinBerlinGermany
| | - Annekathrin M. Keiler
- Institute of Doping Analysis & Sports BiochemistryKreischaGermany
- Environmental Monitoring & Endocrinology, Faculty of BiologyTechnische Universität DresdenDresdenGermany
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6
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Vasconcelos D, Pina A, Habib N, Sousa S. In silico analysis of aptamer-RNA conjugate interactions with human transferrin receptor. Biophys Chem 2024; 314:107308. [PMID: 39208499 DOI: 10.1016/j.bpc.2024.107308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 08/02/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024]
Abstract
The human transmembrane protein Transferrin Receptor-1 is regarded as a promising target for the systemic delivery of therapeutic agents, particularly of nucleic acid therapeutics, such as short double stranded RNAs. This ubiquitous receptor is involved in cellular iron uptake, keeping intracellular homeostasis. It is overexpressed in multiple cancer cell types and is internalized via clathrin-mediated endocytosis. In previous studies, a human transferrin receptor-1 RNA aptamer, identified as TR14 ST1-3, was shown to be capable of effectively internalizing into cells in culture and to deliver small, double stranded RNAs in vitro and in vivo, via systemic administration. To understand, at the molecular level, the aptamer binding to the receptor and the impact of conjugation with the therapeutic RNA, a multi-level in silico protocol was employed, including protein-aptamer docking, molecular dynamics simulations and free energy calculations. The competition for the binding pocket, between the aptamer and the natural ligand human Transferrin, was also evaluated. The results show that the aptamer binds to the same region as Transferrin, with residues from the helical domain showing a critical role. Moreover, the conjugation to the therapeutic RNA, was shown not to affect aptamer binding. Overall, this study provides an atomic-level understanding of aptamer association to human Transferrin Receptor-1 and of its conjugation with a short model-therapeutic RNA, providing also important clues for futures studies aiming to deliver other oligonucleotide-based therapeutics via Transferrin Receptor.
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Affiliation(s)
- Daniel Vasconcelos
- Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK; Apterna Ltd., London SW1P 2PN, UK; Center for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, 4200-319 Porto, Portugal
| | - André Pina
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, BioSIM - Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Nagy Habib
- Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK; Apterna Ltd., London SW1P 2PN, UK
| | - Sérgio Sousa
- Associate Laboratory i4HB - Institute for Health and Bioeconomy, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; UCIBIO - Applied Molecular Biosciences Unit, BioSIM - Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
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7
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Wu Q, Zhu J, Zhang X, Xu X, Luo D, Lin Y, Yan M, Song Y. The antioxidant effect of tetrahedral framework nucleic acid-based delivery of small activating RNA targeting DJ-1 on retinal oxidative stress injury. Cell Prolif 2024; 57:e13635. [PMID: 38594962 PMCID: PMC11294416 DOI: 10.1111/cpr.13635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/07/2024] [Accepted: 03/12/2024] [Indexed: 04/11/2024] Open
Abstract
Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the world's leading causes of blindness. The retinal pigment epithelium (RPE) and vascular endothelial cell exposed to oxidative stress is the major cause of AMD and DR. DJ-1, an important endogenous antioxidant, its overexpression is considered as a promising antioxidant treatment for AMD and DR. Here, we modified the tetrahedral frame nucleic acids (tFNAs) with DJ-1 saRNAs as a delivery system, and synthesized a novel nanocomplex (tFNAs-DJ-1 saRNAs). In vitro studies show that tFNAs-DJ-1 saRNAs can efficiently transfer DJ-1 saRNAs to human umbilical vein endothelial cells (HUVECs) and ARPE-19s, and significantly increased their cellular DJ-1 level. Reactive oxygen species expression in H2O2-treated HUVECs and ARPE-19s were decreased, cell viability was enhanced and cell apoptosis were inhibited when tFNAs-DJ-1 saRNAs were delivered. Moreover, tFNAs-DJ-1 saRNAs preserved mitochondrial structure and function under oxidative stress conditions. In the aspect of molecular mechanism, tFNAs-DJ-1 saRNAs activated Erk and Nrf2 pathway, which might contribute to its protective effects against oxidative stress damage. To conclude, this study shows the successfully establishment of a simple but effective delivery system of DJ-1 saRNAs associated with antioxidant effects in AMD and DR, which may be a promising agent for future treatment in oxidative stress-related retinal disorders.
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Affiliation(s)
- Qiaowei Wu
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Jingyi Zhu
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Xianggui Zhang
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Xiaoxiao Xu
- Innovative Institute of Chinese Medicine and PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Delun Luo
- Innovative Institute of Chinese Medicine and PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Yunfeng Lin
- Department of Maxillofacial Surgery, State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyChengduChina
| | - Ming Yan
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
| | - Yanping Song
- Department of OphthalmologyGeneral Hospital of Central Theater CommandWuhanChina
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Yan J, Zhang H, Li G, Su J, Wei Y, Xu C. Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design. Acta Pharm Sin B 2024; 14:579-601. [PMID: 38322344 PMCID: PMC10840434 DOI: 10.1016/j.apsb.2023.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/24/2023] [Accepted: 10/08/2023] [Indexed: 02/08/2024] Open
Abstract
Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future.
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Affiliation(s)
- Jing Yan
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Institute of Medicine, Shanghai University, Shanghai 200444, China
| | - Hao Zhang
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guangfeng Li
- Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai 200941, China
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Organoid Research Center, Shanghai University, Shanghai 200444, China
| | - Yan Wei
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Organoid Research Center, Shanghai University, Shanghai 200444, China
| | - Can Xu
- Department of Gastroenterology, Changhai Hospital, Shanghai 200433, China
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9
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Ajam-Hosseini M, Akhoondi F, Parvini F, Fahimi H. Gram-negative bacterial sRNAs encapsulated in OMVs: an emerging class of therapeutic targets in diseases. Front Cell Infect Microbiol 2024; 13:1305510. [PMID: 38983695 PMCID: PMC11232669 DOI: 10.3389/fcimb.2023.1305510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 12/26/2023] [Indexed: 07/11/2024] Open
Abstract
Small regulatory RNAs (sRNAs) encapsulated in outer membrane vesicles (OMVs) are critical post-transcriptional regulators of gene expression in prokaryotic and eukaryotic organisms. OMVs are small spherical structures released by Gram-negative bacteria that serve as important vehicles for intercellular communication and can also play an important role in bacterial virulence and host-pathogen interactions. These molecules can interact with mRNAs or proteins and affect various cellular functions and physiological processes in the producing bacteria. This review aims to provide insight into the current understanding of sRNA localization to OMVs in Gram-negative bacteria and highlights the identification, characterization and functional implications of these encapsulated sRNAs. By examining the research gaps in this field, we aim to inspire further exploration and progress in investigating the potential therapeutic applications of OMV-encapsulated sRNAs in various diseases.
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Affiliation(s)
- Mobarakeh Ajam-Hosseini
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Akhoondi
- Department of Molecular Biology of The Cell, Faculty of Bioscience, University of Milan, Milan, Italy
| | - Farshid Parvini
- Department of Biology, Faculty of Basic Sciences, Semnan University, Semnan, Iran
| | - Hossein Fahimi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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10
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Cazares T, Higgs RE, Wang J, Ozer HG. SeedMatchR: identify off-target effects mediated by siRNA seed regions in RNA-seq experiments. Bioinformatics 2024; 40:btae011. [PMID: 38192001 PMCID: PMC10799297 DOI: 10.1093/bioinformatics/btae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 12/20/2023] [Accepted: 01/05/2024] [Indexed: 01/10/2024] Open
Abstract
MOTIVATION On-target gene knockdown, using siRNA, ideally results from binding fully complementary regions in mRNA transcripts to induce direct cleavage. Off-target siRNA gene knockdown can occur through several modes, one being a seed-mediated mechanism mimicking miRNA gene regulation. Seed-mediated off-target effects occur when the ∼8 nucleotides at the 5' end of the guide strand, called a seed region, bind the 3' untranslated regions of mRNA, causing reduced translation. Experiments using siRNA knockdown paired with RNA-seq can be used to detect siRNA sequences with off-target effects driven by the seed region. However, there are limited computational tools designed specifically for detecting siRNA off-target effects mediated by the seed region in differential gene expression experiments. RESULTS SeedMatchR is an R package developed to provide users a single, unified resource for detecting and visualizing seed-mediated off-target effects of siRNA using RNA-seq experiments. SeedMatchR is designed to extend current differential expression analysis tools, such as DESeq2, by annotating results with predicted seed matches. Using publicly available data, we demonstrate the ability of SeedMatchR to detect cumulative changes in differential gene expression attributed to siRNA seed region activity. AVAILABILITY SeedMatchR is available on CRAN. Documentation and example workflows are available through the SeedMatchR GitHub page at https://github.com/tacazares/SeedMatchR.
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Affiliation(s)
- Tareian Cazares
- Genetic Medicine, Eli Lilly and Company, Indianapolis, IN 46225, United States
| | - Richard E Higgs
- Genetic Medicine, Eli Lilly and Company, Indianapolis, IN 46225, United States
| | - Jibo Wang
- Genetic Medicine, Eli Lilly and Company, Indianapolis, IN 46225, United States
| | - Hatice Gulcin Ozer
- Genetic Medicine, Eli Lilly and Company, Indianapolis, IN 46225, United States
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11
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Liu XD, Jin T, Tao Y, Zhang M, Zheng HL, Liu QQ, Yang KH, Wei RN, Li SY, Huang Y, Xue ZY, Hao LY, Wang QH, Yang L, Lin FQ, Shen W, Tao YX, Wang HJ, Cao JL, Pan ZQ. DHX9/DNA-tandem repeat-dependent downregulation of ciRNA-Fmn1 in the dorsal horn is required for neuropathic pain. Acta Pharmacol Sin 2023; 44:1748-1767. [PMID: 37095197 PMCID: PMC10462628 DOI: 10.1038/s41401-023-01082-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/22/2023] [Indexed: 04/26/2023]
Abstract
Circular RNAs (ciRNAs) are emerging as new players in the regulation of gene expression. However, how ciRNAs are involved in neuropathic pain is poorly understood. Here, we identify the nervous-tissue-specific ciRNA-Fmn1 and report that changes in ciRNA-Fmn1 expression in spinal cord dorsal horn neurons play a key role in neuropathic pain after nerve injury. ciRNA-Fmn1 was significantly downregulated in ipsilateral dorsal horn neurons after peripheral nerve injury, at least in part because of a decrease in DNA helicase 9 (DHX9), which regulates production of ciRNA-Fmn1 by binding to DNA-tandem repeats. Blocking ciRNA-Fmn1 downregulation reversed nerve-injury-induced reductions in both the binding of ciRNA-Fmn1 to the ubiquitin ligase UBR5 and the level of ubiquitination of albumin (ALB), thereby abrogating the nerve-injury-induced increase of ALB expression in the dorsal horn and attenuating the associated pain hypersensitivities. Conversely, mimicking downregulation of ciRNA-Fmn1 in naïve mice reduced the UBR5-controlled ubiquitination of ALB, leading to increased expression of ALB in the dorsal horn and induction of neuropathic-pain-like behaviors in naïve mice. Thus, ciRNA-Fmn1 downregulation caused by changes in binding of DHX9 to DNA-tandem repeats contributes to the genesis of neuropathic pain by negatively modulating UBR5-controlled ALB expression in the dorsal horn.
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Affiliation(s)
- Xiao-Dan Liu
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Anesthesiology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, 511518, China
| | - Tong Jin
- Department of Pain, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Yang Tao
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Ming Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Hong-Li Zheng
- Department of Pain, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Qiao-Qiao Liu
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Ke-Hui Yang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Ru-Na Wei
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Si-Yuan Li
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yue Huang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Zhou-Ya Xue
- Department of Anesthesiology, Yancheng Affiliated Hospital of Xuzhou Medical University, Yancheng, 224001, China
| | - Ling-Yun Hao
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Qi-Hui Wang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Li Yang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China
| | - Fu-Qing Lin
- Department of Pain, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China
| | - Wen Shen
- Department of Pain, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China
| | - Yuan-Xiang Tao
- Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA
| | - Hong-Jun Wang
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Jun-Li Cao
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Zhi-Qiang Pan
- Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
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12
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Akçimen F, Lopez ER, Landers JE, Nath A, Chiò A, Chia R, Traynor BJ. Amyotrophic lateral sclerosis: translating genetic discoveries into therapies. Nat Rev Genet 2023; 24:642-658. [PMID: 37024676 PMCID: PMC10611979 DOI: 10.1038/s41576-023-00592-y] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2023] [Indexed: 04/08/2023]
Abstract
Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in turn, fostered the development of putative molecular therapies. In this Review, we outline the current genetic knowledge, emphasizing recent discoveries and emerging concepts such as the implication of distinct types of mutation, variability in mutated genes in diverse genetic ancestries and gene-environment interactions. We also propose a high-level model to synthesize the interdependent effects of genetics, environmental and lifestyle factors, and ageing into a unified theory of ALS. Furthermore, we summarize the current status of therapies developed on the basis of genetic knowledge established for ALS over the past 30 years, and we discuss how developing treatments for ALS will advance our understanding of targeting other neurological diseases.
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Affiliation(s)
- Fulya Akçimen
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
| | - Elia R Lopez
- Therapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - John E Landers
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Avindra Nath
- Section of Infections of the Nervous System, National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Adriano Chiò
- Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy
- Institute of Cognitive Sciences and Technologies, C.N.R, Rome, Italy
- Azienda Ospedaliero Universitaria Citta' della Salute e della Scienza, Turin, Italy
| | - Ruth Chia
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
| | - Bryan J Traynor
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
- Therapeutic Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
- Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
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13
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Szymanowska A, Rodriguez-Aguayo C, Lopez-Berestein G, Amero P. Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment. Noncoding RNA 2023; 9:52. [PMID: 37736898 PMCID: PMC10514839 DOI: 10.3390/ncrna9050052] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/23/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are a group of molecules critical for cell development and growth regulation. They are key regulators of important cellular pathways in the tumor microenvironment. To analyze ncRNAs in the tumor microenvironment, the use of RNA sequencing technology has revolutionized the field. The advancement of this technique has broadened our understanding of the molecular biology of cancer, presenting abundant possibilities for the exploration of novel biomarkers for cancer treatment. In this review, we will summarize recent achievements in understanding the complex role of ncRNA in the tumor microenvironment, we will report the latest studies on the tumor microenvironment using RNA sequencing, and we will discuss the potential use of ncRNAs as therapeutics for the treatment of cancer.
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Affiliation(s)
- Anna Szymanowska
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
| | - Cristian Rodriguez-Aguayo
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
- Center for RNA Interference and Non-Coding RNA, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
- Center for RNA Interference and Non-Coding RNA, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Paola Amero
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; (A.S.); (C.R.-A.); (G.L.-B.)
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14
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Wilton-Clark H, Al-aghbari A, Yang J, Yokota T. Advancing Epidemiology and Genetic Approaches for the Treatment of Spinal and Bulbar Muscular Atrophy: Focus on Prevalence in the Indigenous Population of Western Canada. Genes (Basel) 2023; 14:1634. [PMID: 37628685 PMCID: PMC10454234 DOI: 10.3390/genes14081634] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 08/10/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease among the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on gene therapy and antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.
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Affiliation(s)
- Harry Wilton-Clark
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada;
| | - Ammar Al-aghbari
- Department of Biological Sciences, Faculty of Science, University of Alberta, Edmonton, AB T6G 2R3, Canada;
| | - Jessica Yang
- Department of Immunology, Department of Pharmacology and Toxicology, Faculty of Arts and Science, University of Toronto, Toronto, ON M5S 1A1, Canada;
| | - Toshifumi Yokota
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada;
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15
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Su R, Li C, Wang X, Li Z, Wen Z, Yin Z, Huang G, Liu Y, Yang J, Hu H, Nie H, Zhang K, Fei J. PPFIA1-targeting miR-181a mimic and saRNA overcome imatinib resistance in BCR-ABL1-independent chronic myeloid leukemia by suppressing leukemia stem cell regeneration. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 32:729-742. [PMID: 37234746 PMCID: PMC10208829 DOI: 10.1016/j.omtn.2023.04.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 04/28/2023] [Indexed: 05/28/2023]
Abstract
A large proportion of patients with chronic myeloid leukemia (CML; 20%-50%) develop resistance to imatinib in a BCR-ABL1-independent manner. Therefore, new therapeutic strategies for use in this subset of imatinib-resistant CML patients are urgently needed. In this study, we used a multi-omics approach to show that PPFIA1 was targeted by miR-181a. We demonstrate that both miR-181a and PPFIA1-siRNA reduced the cell viability and proliferative capacity of CML cells in vitro, as well as prolonged the survival of B-NDG mice harboring human BCR-ABL1-independent imatinib-resistant CML cells. Furthermore, treatment with miR-181a mimic and PPFIA1-siRNA inhibited the self-renewal of c-kit+ and CD34+ leukemic stem cells and promoted their apoptosis. Small activating (sa)RNAs targeting the promoter of miR-181a increased the expression of endogenous primitive miR-181a (pri-miR-181a). Transfection with saRNA 1-3 inhibited the proliferation of imatinib-sensitive and -resistant CML cells. However, only saRNA-3 showed a stronger and more sustained inhibitory effect than the miR-181a mimic. Collectively, these results show that miR-181a and PPFIA1-siRNA may overcome the imatinib resistance of BCR-ABL1-independent CML, partially by inhibiting the self-renewal of leukemia stem cells and promoting their apoptosis. Moreover, exogenous saRNAs represent promising therapeutic agents in the treatment of imatinib-resistant BCR-ABL1-independent CML.
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Affiliation(s)
- Rui Su
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Chuting Li
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Xiuyuan Wang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Zhendong Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong, China
| | - Ziqi Wen
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Zhao Yin
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Guiping Huang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Yanjun Liu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Juhua Yang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
| | - Haiyan Hu
- Clinical Trial Center of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Oncology Department of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Hong Nie
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou 510632, China
- Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Keda Zhang
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China
| | - Jia Fei
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China
- Guangdong Engineering Technology Research Center of Drug Development for Small Nucleic Acids, Guangzhou 510632, China
- Antisense Biopharmaceutical Technology Co., Ltd., Guangzhou 510632, China
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16
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Kwofie KD, Hernandez EP, Anisuzzaman, Kawada H, Koike Y, Sasaki S, Inoue T, Jimbo K, Mikami F, Ladzekpo D, Umemiya-Shirafuji R, Yamaji K, Tanaka T, Matsubayashi M, Alim MA, Dadzie SK, Iwanaga S, Tsuji N, Hatta T. RNA activation in ticks. Sci Rep 2023; 13:9341. [PMID: 37291173 PMCID: PMC10250327 DOI: 10.1038/s41598-023-36523-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 06/05/2023] [Indexed: 06/10/2023] Open
Abstract
RNA activation (RNAa) is a burgeoning area of research in which double-stranded RNAs (dsRNAs) or small activating RNAs mediate the upregulation of specific genes by targeting the promoter sequence and/or AU-rich elements in the 3'- untranslated region (3'-UTR) of mRNA molecules. So far, studies on the phenomenon have been limited to mammals, plants, bacteria, Caenorhabditis elegans, and recently, Aedes aegypti. However, it is yet to be applied in other arthropods, including ticks, despite the ubiquitous presence of argonaute 2 protein, which is an indispensable requirement for the formation of RNA-induced transcriptional activation complex to enable a dsRNA-mediated gene activation. In this study, we demonstrated for the first time the possible presence of RNAa phenomenon in the tick vector, Haemaphysalis longicornis (Asian longhorned tick). We targeted the 3'-UTR of a novel endochitinase-like gene (HlemCHT) identified previously in H. longicornis eggs for dsRNA-mediated gene activation. Our results showed an increased gene expression in eggs of H. longicornis endochitinase-dsRNA-injected (dsHlemCHT) ticks on day-13 post-oviposition. Furthermore, we observed that eggs of dsHlemCHT ticks exhibited relatively early egg development and hatching, suggesting a dsRNA-mediated activation of the HlemCHT gene in the eggs. This is the first attempt to provide evidence of RNAa in ticks. Although further studies are required to elucidate the detailed mechanism by which RNAa occurs in ticks, the outcome of this study provides new opportunities for the use of RNAa as a gene overexpression tool in future studies on tick biology, to reduce the global burden of ticks and tick-borne diseases.
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Affiliation(s)
- Kofi Dadzie Kwofie
- Department of Parasitology and Tropical Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, P.O. Box LG 581, Legon, Accra, Ghana
| | - Emmanuel Pacia Hernandez
- Department of Parasitology and Tropical Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan
- Department of Veterinary Paraclinical Sciences, College of Veterinary Medicine, University of the Philippines at Los Baños, College, 4031, Laguna, Philippines
| | - Anisuzzaman
- Department of Parasitology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh
| | - Hayato Kawada
- Department of Parasitology and Tropical Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan
- Department of Molecular and Cellular Parasitology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yuki Koike
- Department of Molecular and Cellular Parasitology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Sana Sasaki
- Department of Molecular and Cellular Parasitology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Takahiro Inoue
- Department of Molecular and Cellular Parasitology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Kei Jimbo
- Department of Molecular and Cellular Parasitology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Fusako Mikami
- Department of Parasitology and Tropical Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan
| | - Danielle Ladzekpo
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, P.O. Box LG 581, Legon, Accra, Ghana
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Rika Umemiya-Shirafuji
- National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido, 080-8555, Japan
| | - Kayoko Yamaji
- Department of Tropical Medicine and Center for Medical Entomology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-8461, Japan
| | - Tetsuya Tanaka
- Laboratory of Infectious Diseases, Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, 890-0065, Japan
| | - Makoto Matsubayashi
- Department of Veterinary Immunology, Graduate School of Veterinary Sciences, Osaka Metropolitan University, Izumisano, Osaka, 598-8531, Japan
| | - Md Abdul Alim
- Department of Parasitology, Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh
| | - Samuel Kweku Dadzie
- Department of Parasitology, Noguchi Memorial Institute for Medical Research, College of Health Sciences, University of Ghana, P.O. Box LG 581, Legon, Accra, Ghana
| | - Shiroh Iwanaga
- Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka, 565-0871, Japan
- Center for Infectious Disease Education and Research (CIDER), Osaka University, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Naotoshi Tsuji
- Department of Parasitology and Tropical Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan
- Department of Molecular and Cellular Parasitology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Takeshi Hatta
- Department of Parasitology and Tropical Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan.
- Department of Molecular and Cellular Parasitology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan.
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17
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Chen L, Wang Y. Interdisciplinary advances reshape the delivery tools for effective NASH treatment. Mol Metab 2023; 73:101730. [PMID: 37142161 DOI: 10.1016/j.molmet.2023.101730] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/10/2023] [Accepted: 04/20/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH), a severe systemic and inflammatory subtype of nonalcoholic fatty liver disease, eventually develops into cirrhosis and hepatocellular carcinoma with few options for effective treatment. Currently potent small molecules identified in preclinical studies are confronted with adverse effects and long-term ineffectiveness in clinical trials. Nevertheless, highly specific delivery tools designed from interdisciplinary concepts may address the significant challenges by either effectively increasing the concentrations of drugs in target cell types, or selectively manipulating the gene expression in liver to resolve NASH. SCOPE OF REVIEW We focus on dissecting the detailed principles of the latest interdisciplinary advances and concepts that direct the design of future delivery tools to enhance the efficacy. Recent advances have indicated that cell and organelle-specific vehicles, non-coding RNA research (e.g. saRNA, hybrid miRNA) improve the specificity, while small extracellular vesicles and coacervates increase the cellular uptake of therapeutics. Moreover, strategies based on interdisciplinary advances drastically elevate drug loading capacity and delivery efficiency and ameliorate NASH and other liver diseases. MAJOR CONCLUSIONS The latest concepts and advances in chemistry, biochemistry and machine learning technology provide the framework and strategies for the design of more effective tools to treat NASH, other pivotal liver diseases and metabolic disorders.
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Affiliation(s)
- Linshan Chen
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China
| | - Yibing Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China; Shanghai Frontiers Science Research Base of Exercise and Metabolic Health.
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18
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Sufian MA, Ilies MA. Lipid-based nucleic acid therapeutics with in vivo efficacy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1856. [PMID: 36180107 PMCID: PMC10023279 DOI: 10.1002/wnan.1856] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/22/2022] [Accepted: 08/30/2022] [Indexed: 03/09/2023]
Abstract
Synthetic vectors for therapeutic nucleic acid delivery are currently competing significantly with their viral counter parts due to their reduced immunogenicity, large payload capacity, and ease of manufacture under GMP-compliant norms. The approval of Onpattro, a lipid-based siRNA therapeutic, and the proven clinical success of two lipid-based COVID-19 vaccines from Pfizer-BioNTech, and Moderna heralded the specific advantages of lipid-based systems among all other synthetic nucleic acid carriers. Lipid-based systems with diverse payloads-plasmid DNA (pDNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), and messenger RNA (mRNA)-are now becoming a mature technology, with growing impact in the clinic. Research over four decades identified the key factors determining the therapeutic success of these multi-component systems. Here, we discuss the main nucleic acid-based technologies, presenting their mechanism of action, delivery barriers facing them, the structural properties of the payload as well as the component lipids that regulate physicochemical properties, pharmacokinetics and biodistribution, efficacy, and toxicity of the resultant nanoparticles. We further detail on the formulation parameters, evolution of the manufacturing techniques that generate reproducible and scalable outputs, and key manufacturing aspects that enable control over physicochemical properties of the resultant particles. Preclinical applications of some of these formulations that were successfully translated from in vitro studies to animal models are subsequently discussed. Finally, clinical success and failure of these systems starting from 1993 to present are highlighted, in a holistic literature review focused on lipid-based nucleic acid delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
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Affiliation(s)
- Md Abu Sufian
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
| | - Marc A. Ilies
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
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19
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Togawa H, Okubo T, Nonaka Y, Yamaguchi T, Obika S. Retention behavior of short double-stranded oligonucleotide and its potential impurities by anion-exchange chromatography under non-denaturing conditions. J Chromatogr A 2023; 1691:463808. [PMID: 36706652 DOI: 10.1016/j.chroma.2023.463808] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/04/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023]
Abstract
Small interfering RNA (siRNA), consisting of two complementary single-stranded RNAs with overhanging bases, is being adopted as a potent and specific inhibitor of target gene expression. However, non-duplexed single strands and undesired double strands composed of impurities (e.g., n-1 mer) could be produced in addition to the target double strand in the siRNA manufacturing process. Compared to the liquid chromatography analysis of single strands, the analysis of the duplexes under non-denaturing conditions is challenging, since restricted chromatographic conditions are required to maintain the Watson-Crick hydrogen bonds. This study reports the analysis of double-stranded oligomers having approximately 20 base pairs with some overhanging bases as non-denatured forms by anion-exchange chromatography (AEX). Optimization of the chromatographic conditions could potentially achieve the adequate separation of excess single strands from the double strand. Non-optimal duplexes, such as duplexes with long overhangs or bulge structures, were prepared by intentionally deleting terminal or middle nucleotide(s) of either the sense or the antisense strand, and these non-optimal duplexes were eluted at different retention times in most of the cases. Interestingly, under alkaline chromatographic conditions (pH 9.0), non-optimal duplexes containing a shortmer tended to exhibit a stronger retention than their parent duplexes, although they possessed a less negative charge. This study demonstrated some retention behavior of double strands with overhangs by AEX under non-denaturing conditions.
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Affiliation(s)
- Hiroyuki Togawa
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; CERI Hita, Chemicals Evaluation and Research Institute, Japan, 3-822 Ishii-machi, Hita, Oita 877-0061, Japan
| | - Takashi Okubo
- CERI Hita, Chemicals Evaluation and Research Institute, Japan, 3-822 Ishii-machi, Hita, Oita 877-0061, Japan
| | - Yumi Nonaka
- CERI Kurume, Chemicals Evaluation and Research Institute, Japan, 3-2-7 Miyanojin, Kurume, Fukuoka 839-0801, Japan
| | - Takao Yamaguchi
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Satoshi Obika
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
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20
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Saini S, Khurana S, Saini D, Rajput S, Thakur CJ, Singh J, Jaswal A, Kapoor Y, Kumar V, Saini A. In silico analysis of genomic landscape of SARS-CoV-2 and its variant of concerns (Delta and Omicron) reveals changes in the coding potential of miRNAs and their target genes. Gene 2023; 853:147097. [PMID: 36470485 PMCID: PMC9721428 DOI: 10.1016/j.gene.2022.147097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
COVID-19 related morbidities and mortalities are still continued due to the emergence of new variants of SARS-CoV-2. In the last few years, viral miRNAs have been the centre of study to understand the disease pathophysiology. In this work, we aimed to predict the change in coding potential of the viral miRNAs in SARS-CoV-2's VOCs, Delta and Omicron compared to the Reference (Wuhan origin) strain using bioinformatics tools. After ab-intio based screening by the Vmir tool and validation, we retrieved 22, 6, and 6 pre-miRNAs for Reference, Delta, and Omicron. Most of the predicted unique pre-miRNAs of Delta and Omicron were found to be encoded from the terminal and origin of the genomic sequence, respectively. Mature miRNAs identified by MatureBayes from the unique pre-miRNAs were used for target identification using miRDB. A total of 1786, 216, and 143 high-confidence target genes were captured for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis. The GO and KEGG pathways terms analysis revealed the involvement of Delta miRNAs targeted genes in the pathways such as Human cytomegalovirus infection, Breast cancer, Apoptosis, Neurotrophin signaling, and Axon guidance whereas the Sphingolipid signaling pathway was found for the Omicron. Furthermore, we focussed our analysis on target genes that were validated through GEO's (Gene Expression Omnibus) DEGs (Differentially Expressed Genes) dataset, in which FGL2, TNSF12, OGN, GDF11, and BMP11 target genes were found to be down-regulated by Reference miRNAs and YAE1 and RSU1 by Delta. Few genes were also observed to be validated among in up-regulated gene set of the GEO dataset, in which MMP14, TNFRSF21, SGMS1, and TMEM192 were related to Reference whereas ZEB2 was detected in all three strains. This study thus provides an in-silico based analysis that deciphered the unique pre-miRNAs in Delta and Omicron compared to Reference. However, the findings need future wet lab studies for validation.
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Affiliation(s)
- Sandeep Saini
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India; Department of Biophysics, Panjab University, Sector 25, Chandigarh 160014, India.
| | - Savi Khurana
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India
| | - Dikshant Saini
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India
| | - Saru Rajput
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India
| | - Chander Jyoti Thakur
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India
| | - Jeevisha Singh
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India
| | - Akanksha Jaswal
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India
| | - Yogesh Kapoor
- Department of Engineering and Technology, Shoolini University, Solan, Himachal Pradesh, India
| | - Varinder Kumar
- Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Sector 32, Chandigarh 160030, India
| | - Avneet Saini
- Department of Biophysics, Panjab University, Sector 25, Chandigarh 160014, India.
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21
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Zhang M, Lin D, Luo C, Wei P, Cui K, Chen K, Chen Z. saKLK1-374 is more difficult to induce KLK1 expression in normal prostate cell lines than that in prostate cancer cell lines: Rethinking the universality of RNA activation. Biochem Biophys Res Commun 2023; 643:157-168. [PMID: 36610381 DOI: 10.1016/j.bbrc.2022.12.075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/17/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022]
Abstract
RNA activation, as a method of regulating gene expression at the transcriptional level, is far less widely used than RNA interference because of the insufficient understanding of the mechanism and the unstable success rate. It is necessary to analyze the failure cases of RNA activation to promote the application of RNA activation. When we validated the saRNAs designed to induce KLK1 expression, we found that saKLK1-374 can upregulate KLK1 expression in prostate tumor cell lines, but failed in normal prostate cell lines. To determine whether the RNA activation of normal cells is difficult only when the target gene is KLK1, we tested p21WAF1/CIP1 as the target gene in RNA activation experiments of normal and cancer prostate cells. Next, to determine whether the above phenomenon exists in other tissues, we used normal and cancerous bladder cells to perform RNA activation experiments with KLK1 and p21WAF1/CIP1 as targets. We have also extended the time from transfection to detection to evaluate whether a longer incubation time can make saRNA upregulate the target genes in normal cells. Fluorescently labeled dsRNA was transfected to evaluate the transfection efficiency, and the expression of Ago2 and IPO8 necessary for RNA activation was also detected. The p21WAF1/CIP1 could be significantly upregulated by saRNA in prostate cancer cells, but not in normal prostate cells. The expression of KLK1 in bladder-derived cell lines was extremely low and could not be induced by saRNA. The p21WAF1/CIP1 was upregulated by saRNA to a higher extent in bladder cancer cells but to a lower extent in normal bladder cells. Prolonging incubation time could not make saRNA induce the expression of target genes in normal cells. Compared with tumor cells used in this study, normal cells had lower transfection efficiency or lower expression of Ago2 and IPO8. Although it has been currently found that normal cell lines in the prostate and bladder might be more difficult to be successfully induced target gene expression by exogenous saRNA than tumor cells due to low transfection efficiency or Ago2 and IPO8 expression, it is not certain that this phenomenon occurs in other types of tissue. However, researchers still need to pay attention to the transfection efficiency and/or the expression levels of Ago2 and IPO8 when conducting RNA activation experiments in normal cells.
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Affiliation(s)
- Mengyang Zhang
- Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China
| | - Dongxu Lin
- Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China
| | - Changcheng Luo
- Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China
| | - Pengyu Wei
- Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China
| | - Kai Cui
- Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China
| | - Ke Chen
- Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China
| | - Zhong Chen
- Department of Urology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, 430030, Hubei, China.
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22
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Future regenerative medicine developments and their therapeutic applications. Biomed Pharmacother 2023; 158:114131. [PMID: 36538861 DOI: 10.1016/j.biopha.2022.114131] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Although the currently available pharmacological assays can cure most pathological disorders, they have limited therapeutic value in relieving certain disorders like myocardial infarct, peripheral vascular disease, amputated limbs, or organ failure (e.g. renal failure). Pilot studies to overcome such problems using regenerative medicine (RM) delivered promising data. Comprehensive investigations of RM in zebrafish or reptilians are necessary for better understanding. However, the precise mechanisms remain poorly understood despite the tremendous amount of data obtained using the zebrafish model investigating the exact mechanisms behind their regenerative capability. Indeed, understanding such mechanisms and their application to humans can save millions of lives from dying due to potentially life-threatening events. Recent studies have launched a revolution in replacing damaged human organs via different approaches in the last few decades. The newly established branch of medicine (known as Regenerative Medicine aims to enhance natural repair mechanisms. This can be done through the application of several advanced broad-spectrum technologies such as organ transplantation, tissue engineering, and application of Scaffolds technology (support vascularization using an extracellular matrix), stem cell therapy, miRNA treatment, development of 3D mini-organs (organoids), and the construction of artificial tissues using nanomedicine and 3D bio-printers. Moreover, in the next few decades, revolutionary approaches in regenerative medicine will be applied based on artificial intelligence and wireless data exchange, soft intelligence biomaterials, nanorobotics, and even living robotics capable of self-repair. The present work presents a comprehensive overview that summarizes the new and future advances in the field of RM.
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23
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Guerriaud M, Kohli E. RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European union legislation. Front Med (Lausanne) 2022; 9:1012497. [PMID: 36325384 PMCID: PMC9618588 DOI: 10.3389/fmed.2022.1012497] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/26/2022] [Indexed: 11/14/2022] Open
Abstract
Many RNA-based drugs, both vaccines and non-vaccines, are under development or even approved. They include coding mRNAs and non-coding (nc) RNAs among them antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), micro-RNAs (miRNAs), small activating RNAs (saRNAs), RNA aptamers and RNA guides. According to the European Union (EU) legislation, these products can be currently categorized into different regulatory statuses, depending, for vaccines, on their target (infectious disease or not) and, for other drugs, on how they are obtained (chemically or biologically). This classification is fundamental to the type of marketing authorization (MA), and therefore to the controls to be performed, from preclinical stages through clinical trials to pharmacovigilance, to meet the safety requirements for patients. However, the current rules raise several problems, in particular the risk, because technology is evolving, to have similar RNA drugs being covered by very different legal statuses and the lack of international harmonization. The objectives of this study are (i) to review how RNA medicinal products are currently legally categorized in the EU and especially whether they fall under the status of gene therapy medicinal products (GTMP), a regulatory status belonging to advanced therapy medicinal products (ATMP), (ii) to discuss the issues generated by this classification, with a focus on the heterogeneity of statuses of these products, the differences with the American and ICH definitions and the potential impact on the safety requirements.
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Affiliation(s)
- Mathieu Guerriaud
- CREDIMI Laboratory EA 7532 and Laboratory of Excellence LipSTIC ANR-11-LABX-0021, Faculty of Health Sciences (Pharmacy), University of Burgundy, Dijon, France
- *Correspondence: Mathieu Guerriaud,
| | - Evelyne Kohli
- UMR INSERM/uB/AGROSUP 1231, Team 3 HSP-Pathies, Labelled Ligue Nationale Contre le Cancer and Laboratory of Excellence LipSTIC ANR-11-LABX-0021, Faculty of Health Sciences (Pharmacy), University of Burgundy, Dijon, France
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24
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Xiong Y, Ke R, Zhang Q, Lan W, Yuan W, Chan KNI, Roussel T, Jiang Y, Wu J, Liu S, Wong AST, Shim JS, Zhang X, Xie R, Dusetti N, Iovanna J, Habib N, Peng L, Lee LTO. Small Activating RNA Modulation of the G Protein-Coupled Receptor for Cancer Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200562. [PMID: 35712764 PMCID: PMC9475523 DOI: 10.1002/advs.202200562] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/23/2022] [Indexed: 06/15/2023]
Abstract
G protein-coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor-xenografted mouse models and patient-derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.
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Affiliation(s)
- Yunfang Xiong
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Ran Ke
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Qingyu Zhang
- Department of Obstetrics and GynaecologyAffiliated Hospital of Guangdong Medical UniversityZhanjiangGuangdong524001China
| | - Wenjun Lan
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Wanjun Yuan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Karol Nga Ieng Chan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Tom Roussel
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Yifan Jiang
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Jing Wu
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Shuai Liu
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Alice Sze Tsai Wong
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
| | - Joong Sup Shim
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Xuanjun Zhang
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Ruiyu Xie
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Nagy Habib
- Department of Surgery and CancerImperial College LondonLondonW12 0NNUK
- MiNA Therapeutics, Translation & Innovation Hub80 Wood LaneLondonW12 0BZUK
| | - Ling Peng
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Leo Tsz On Lee
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
- Centre of Reproduction, Development, and AgingFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
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25
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Nteli P, Bajwa DE, Politakis D, Michalopoulos C, Kefala-Narin A, Efstathopoulos EP, Gazouli M. Nanomedicine approaches for treatment of hematologic and oncologic malignancies. World J Clin Oncol 2022; 13:553-566. [PMID: 36157164 PMCID: PMC9346428 DOI: 10.5306/wjco.v13.i7.553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/10/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is a leading cause of death worldwide. Nowadays, the therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality. Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer. Immunotherapy is revolutionizing cancer treatment, as it can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities (as in the case of the nanodrug Ferumoxytol). Furthermore, the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside. The most common example includes lipid-based nanoparticles that target VEGF-Α and KRAS pathways. This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies. The insights provided and the evidence obtained in this paper indicate a bright future ahead for immuno-oncology applications of engineering nanomedicines.
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Affiliation(s)
- Polyxeni Nteli
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Danae Efremia Bajwa
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Dimitrios Politakis
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Charalampos Michalopoulos
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Anastasia Kefala-Narin
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Efstathios P Efstathopoulos
- 2nd Department of Radiology, Medical School, National and Kapodistrian University of Athens, General University Hospital Attikon, Athens12462, Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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26
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Bege M, Borbás A. The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides. Pharmaceuticals (Basel) 2022; 15:ph15080909. [PMID: 35893733 PMCID: PMC9330994 DOI: 10.3390/ph15080909] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/17/2022] [Accepted: 07/20/2022] [Indexed: 02/04/2023] Open
Abstract
Nucleic acids play a central role in human biology, making them suitable and attractive tools for therapeutic applications. While conventional drugs generally target proteins and induce transient therapeutic effects, nucleic acid medicines can achieve long-lasting or curative effects by targeting the genetic bases of diseases. However, native oligonucleotides are characterized by low in vivo stability due to nuclease sensitivity and unfavourable physicochemical properties due to their polyanionic nature, which are obstacles to their therapeutic use. A myriad of synthetic oligonucleotides have been prepared in the last few decades and it has been shown that proper chemical modifications to either the nucleobase, the ribofuranose unit or the phosphate backbone can protect the nucleic acids from degradation, enable efficient cellular uptake and target localization ensuring the efficiency of the oligonucleotide-based therapy. In this review, we present a summary of structure and properties of artificial nucleic acids containing nucleobase, sugar or backbone modifications, and provide an overview of the structure and mechanism of action of approved oligonucleotide drugs including gene silencing agents, aptamers and mRNA vaccines.
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Affiliation(s)
- Miklós Bege
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
- Institute of Healthcare Industry, University of Debrecen, Nagyerdei körút 98, 4032 Debrecen, Hungary
- MTA-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
| | - Anikó Borbás
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
- National Laboratory of Virology, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary
- Correspondence:
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27
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Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease for which there is currently no robust therapy. Recent progress in understanding ALS disease mechanisms and genetics in combination with innovations in gene modulation strategies creates promising new options for the development of ALS therapies. In recent years, six gene modulation therapies have been tested in ALS patients. These target gain-of-function pathology of the most common ALS genes, SOD1, C9ORF72, FUS, and ATXN2, using adeno-associated virus (AAV)-mediated microRNAs and antisense oligonucleotides (ASOs). Here, we review the latest clinical and preclinical advances in gene modulation approaches for ALS, including gene silencing, gene correction, and gene augmentation. These techniques have the potential to positively impact the direction of future research trials and transform ALS treatments for this grave disease.
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Affiliation(s)
- Katharina E Meijboom
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| | - Robert H Brown
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
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28
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Lim SA, Cox A, Tung M, Chung EJ. Clinical progress of nanomedicine-based RNA therapies. Bioact Mater 2022; 12:203-213. [PMID: 35310381 PMCID: PMC8897211 DOI: 10.1016/j.bioactmat.2021.10.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/11/2021] [Accepted: 10/14/2021] [Indexed: 12/14/2022] Open
Abstract
The clinical application of nanoparticles (NPs) to deliver RNA for therapy has progressed rapidly since the FDA approval of Onpattro® in 2018 for the treatment of polyneuropathy associated with hereditary transthyretin amyloidosis. The emergency use authorization or approval and widespread global use of two mRNA-NP based vaccines developed by Moderna Therapeutics Inc. and Pfizer-BioNTech in 2021 has highlighted the translatability of NP technology for RNA delivery. Furthermore, in clinical trials, a wide variety of NP formulations have been found to extend the half-life of RNA molecules such as microRNA, small interfering RNA, and messenger RNA, with limited safety issues. In this review, we discuss the NP formulations that are already used in the clinic to deliver therapeutic RNA and highlight examples of RNA-NPs which are currently under evaluation for human use. We also detail NP formulations that failed to progress through clinical trials, in hopes of guiding future successful translation of nanomedicine-based RNA therapeutics into the clinic.
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Affiliation(s)
- Siyoung A. Lim
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Alysia Cox
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Madelynn Tung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
| | - Eun Ji Chung
- Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA, USA
- Department of Medicine, Division of Nephrology and Hypertension, University of Southern California, Los Angeles, CA, USA
- Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, University of Southern California, Los Angeles, CA, USA
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29
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Sasso J, Ambrose BJB, Tenchov R, Datta RS, Basel MT, DeLong RK, Zhou QA. The Progress and Promise of RNA Medicine─An Arsenal of Targeted Treatments. J Med Chem 2022; 65:6975-7015. [PMID: 35533054 PMCID: PMC9115888 DOI: 10.1021/acs.jmedchem.2c00024] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Indexed: 02/08/2023]
Abstract
In the past decade, there has been a shift in research, clinical development, and commercial activity to exploit the many physiological roles of RNA for use in medicine. With the rapid success in the development of lipid-RNA nanoparticles for mRNA vaccines against COVID-19 and with several approved RNA-based drugs, RNA has catapulted to the forefront of drug research. With diverse functions beyond the role of mRNA in producing antigens or therapeutic proteins, many classes of RNA serve regulatory roles in cells and tissues. These RNAs have potential as new therapeutics, with RNA itself serving as either a drug or a target. Here, based on the CAS Content Collection, we provide a landscape view of the current state and outline trends in RNA research in medicine across time, geography, therapeutic pipelines, chemical modifications, and delivery mechanisms.
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Affiliation(s)
- Janet
M. Sasso
- CAS,
a division of the American Chemical Society 2540 Olentangy River Road, Columbus, Ohio 43202, United States
| | - Barbara J. B. Ambrose
- CAS,
a division of the American Chemical Society 2540 Olentangy River Road, Columbus, Ohio 43202, United States
| | - Rumiana Tenchov
- CAS,
a division of the American Chemical Society 2540 Olentangy River Road, Columbus, Ohio 43202, United States
| | - Ruchira S. Datta
- CAS,
a division of the American Chemical Society 2540 Olentangy River Road, Columbus, Ohio 43202, United States
| | - Matthew T. Basel
- College
of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States
| | - Robert K. DeLong
- Nanotechnology
Innovation Center Kansas State, Kansas State
University, Manhattan, Kansas 66506, United States
| | - Qiongqiong Angela Zhou
- CAS,
a division of the American Chemical Society 2540 Olentangy River Road, Columbus, Ohio 43202, United States
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30
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Bruch A, Kelani AA, Blango MG. RNA-based therapeutics to treat human fungal infections. Trends Microbiol 2022; 30:411-420. [PMID: 34635448 PMCID: PMC8498853 DOI: 10.1016/j.tim.2021.09.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 09/03/2021] [Accepted: 09/14/2021] [Indexed: 01/09/2023]
Abstract
In recent decades, RNA-based therapeutics have transitioned from a near impossibility to a compelling treatment alternative for genetic disorders and infectious diseases. The mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are truly groundbreaking, and new adaptations are already being proposed to fight other microbes. Unfortunately, the potential of RNA-based therapeutics to treat human fungal infections has remained mostly absent from the conversation, despite the fact that invasive fungal infections kill as many per year as tuberculosis and even more than malaria. Here, we argue that RNA-based therapeutics should be investigated for the treatment of human fungal infections and discuss several major roadblocks and potential circumventions that may allow for the realization of RNA-based therapies against human fungal pathogens.
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Affiliation(s)
- Alexander Bruch
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Abdulrahman A. Kelani
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Matthew G. Blango
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Leibniz-HKI), Jena, Germany,Correspondence:
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Robinson EL, Baker AH, Brittan M, McCracken I, Condorelli G, Emanueli C, Srivastava PK, Gaetano C, Thum T, Vanhaverbeke M, Angione C, Heymans S, Devaux Y, Pedrazzini T, Martelli F, EU-CardioRNA COST Action CA17129. Dissecting the transcriptome in cardiovascular disease. Cardiovasc Res 2022; 118:1004-1019. [PMID: 33757121 PMCID: PMC8930073 DOI: 10.1093/cvr/cvab117] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
The human transcriptome comprises a complex network of coding and non-coding RNAs implicated in a myriad of biological functions. Non-coding RNAs exhibit highly organized spatial and temporal expression patterns and are emerging as critical regulators of differentiation, homeostasis, and pathological states, including in the cardiovascular system. This review defines the current knowledge gaps, unmet methodological needs, and describes the challenges in dissecting and understanding the role and regulation of the non-coding transcriptome in cardiovascular disease. These challenges include poor annotation of the non-coding genome, determination of the cellular distribution of transcripts, assessment of the role of RNA processing and identification of cell-type specific changes in cardiovascular physiology and disease. We highlight similarities and differences in the hurdles associated with the analysis of the non-coding and protein-coding transcriptomes. In addition, we discuss how the lack of consensus and absence of standardized methods affect reproducibility of data. These shortcomings should be defeated in order to make significant scientific progress and foster the development of clinically applicable non-coding RNA-based therapeutic strategies to lessen the burden of cardiovascular disease.
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Affiliation(s)
- Emma L Robinson
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 Maastricht University, Maastricht, The Netherlands
- The Division of Cardiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Andrew H Baker
- Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Mairi Brittan
- Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - Ian McCracken
- Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
| | - G Condorelli
- Humanitas Research Hospital, Humanitas University, Via Manzoni 113, Rozzano, MI 20089, Italy
| | - C Emanueli
- Imperial College, National Heart and Lung Institute, Hammersmith campus, Du Cane Road, London W12 0NN, UK
| | - P K Srivastava
- Imperial College, National Heart and Lung Institute, Hammersmith campus, Du Cane Road, London W12 0NN, UK
| | - C Gaetano
- Laboratorio di Epigenetica, Istituti Clinici Scientifici Maugeri IRCCS, Via Maugeri 4, Pavia 27100, Italy
| | - T Thum
- Hannover Medical School, Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Carl-Neuberg-Straße 1 30625 Hannover, Germany
| | - M Vanhaverbeke
- UZ Gasthuisberg Campus, KU Leuven, Herestraat 49 3000 Leuven, Belgium
| | - C Angione
- Department of Computer Science and Information Systems, Teesside University, Middlesbrough, TS4 3BX, UK
| | - S Heymans
- Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Universiteitssingel 50, 6229 Maastricht University, Maastricht, The Netherlands
| | - Y Devaux
- Cardiovascular Research Unit, Department of Population Health, Luxembourg Institute of Health, 1A-B, rue Thomas Edison, L-1445 Strassen, Luxembourg
| | - T Pedrazzini
- Experimental Cardiology Unit, Division of Cardiology, Department of Cardiovascular Medicine, University of Lausanne Medical School, 1011 Lausanne, Switzerland
| | - F Martelli
- Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Piazza Edmondo Malan, 2, 20097 San Donato, Milan, Italy
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Zhang YL, Kang M, Wu JC, Xie MY, Xue RY, Tang Q, Yang H, Li LC. Small activating RNA activation of ATOH1 promotes regeneration of human inner ear hair cells. Bioengineered 2022; 13:6729-6739. [PMID: 35246011 PMCID: PMC8974106 DOI: 10.1080/21655979.2022.2045835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The loss of inner ear hair cells leads to irreversible acoustic injury in mammals, and regeneration of inner ear hair cells to restore hearing loss is challenging. ATOH1 is a key gene in the development and regeneration of hair cells. Small activating RNAs (saRNAs) can target a gene to specifically upregulate its expression. This study aimed to explore whether small activating RNAs could induce the differentiation of human adipose-derived mesenchymal stem cells into hair cell-like cells with a combination of growth factors in vitro and thus provide a new strategy for hair cell regeneration and the treatment of sensorineural hearing loss. Fifteen small activating RNAs targeting the human ATOH1 gene were designed and screened in 293 T and human adipose-derived mesenchymal stem cells, and 3 of these candidates were found to be capable of effectively and stably activating ATOH1 gene expression. The selected small activating RNAs were then transfected into hair cell progenitor cells, and hair cell markers were examined 10 days after transfection. After transfection of the selected small activating RNAs, the expression of the characteristic markers of inner ear hair cells, POU class 4 homeobox 3 (POU4F3) and myosin VIIA (MYO7A), was detected. Human adipose-derived mesenchymal stem cells have the potential to differentiate into human hair cell progenitor cells. In vitro, small activating RNAs were able to induce the differentiation of hair cell progenitor cells into hair cell-like cells. Therefore, RNA activation technology has the potential to provide a new strategy for the regeneration of hair cells.
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Affiliation(s)
- Yong-Li Zhang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Moorim Kang
- Ractigen Therapeutics, Nantong, Jiangsu, China
| | | | - Meng-Yao Xie
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Ruo-Yan Xue
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Qi Tang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Hua Yang
- Department of Otolaryngology, Peking Union Medical College and Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Long-Cheng Li
- Ractigen Therapeutics, Nantong, Jiangsu, China.,Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, Jiangsu, China
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Van de Vyver T, De Smedt SC, Raemdonck K. Modulating intracellular pathways to improve non-viral delivery of RNA therapeutics. Adv Drug Deliv Rev 2022; 181:114041. [PMID: 34763002 DOI: 10.1016/j.addr.2021.114041] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/12/2021] [Accepted: 11/02/2021] [Indexed: 12/12/2022]
Abstract
RNA therapeutics (e.g. siRNA, oligonucleotides, mRNA, etc.) show great potential for the treatment of a myriad of diseases. However, to reach their site of action in the cytosol or nucleus of target cells, multiple intra- and extracellular barriers have to be surmounted. Several non-viral delivery systems, such as nanoparticles and conjugates, have been successfully developed to meet this requirement. Unfortunately, despite these clear advances, state-of-the-art delivery agents still suffer from relatively low intracellular delivery efficiencies. Notably, our current understanding of the intracellular delivery process is largely oversimplified. Gaining mechanistic insight into how RNA formulations are processed by cells will fuel rational design of the next generation of delivery carriers. In addition, identifying which intracellular pathways contribute to productive RNA delivery could provide opportunities to boost the delivery performance of existing nanoformulations. In this review, we discuss both established as well as emerging techniques that can be used to assess the impact of different intracellular barriers on RNA transfection performance. Next, we highlight how several modulators, including small molecules but also genetic perturbation technologies, can boost RNA delivery by intervening at differing stages of the intracellular delivery process, such as cellular uptake, intracellular trafficking, endosomal escape, autophagy and exocytosis.
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Affiliation(s)
- Thijs Van de Vyver
- Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
| | - Stefaan C De Smedt
- Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
| | - Koen Raemdonck
- Ghent Research Group on Nanomedicines, Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
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34
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Tarab-Ravski D, Stotsky-Oterin L, Peer D. Delivery strategies of RNA therapeutics to leukocytes. J Control Release 2022; 342:362-371. [PMID: 35041904 DOI: 10.1016/j.jconrel.2022.01.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/31/2021] [Accepted: 01/10/2022] [Indexed: 12/27/2022]
Abstract
Harnessing RNA-based therapeutics for cancer, inflammation, and viral diseases is hindered by poor delivery of therapeutic RNA molecules. Targeting leukocytes to treat these conditions holds great promise, as they are key participants in their initiation, drug response, and treatment. The various extra- and intra-cellular obstacles that impediment the clinical implementation of therapeutic RNA can be overcome by utilizing drug delivery systems. However, delivery of therapeutic RNA to leukocytes poses an even greater challenge as these cells are difficult to reach and transfect upon systemic administration. This review briefly describes the existing successful delivery strategies that efficiently target leukocytes in vivo and discuss their potential clinical applicability.
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Affiliation(s)
- Dana Tarab-Ravski
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel
| | - Lior Stotsky-Oterin
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel
| | - Dan Peer
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, Israel; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Materials Sciences & Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv, Israel; Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.
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35
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Small activating RNA-activated NIS gene promotes 131I uptake and inhibits thyroid cancer via AMPK/mTOR pathway. Pathol Res Pract 2021; 229:153735. [PMID: 34922208 DOI: 10.1016/j.prp.2021.153735] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND Sodium/iodide symporter (NIS) acts as a vital role in regulation of iodide uptake in thyroid cancer. However, the efficient approach to increase NIS expression and the mechanism of NIS-mediated iodide uptake in thyroid cancer remain unclear. METHODS Small activating RNA (saRNA) was used to promote NIS expression. And the cell viability, apoptosis, and autophagy were detected using Cell count-kit 8 (CCK-8), Annexin V-FITC/PI double staining, and GFP-LC3 immunofluorescence assays, respectively. The protein levels of caspase 3, Bax, Bcl-2, ATG5, ATG12, LC3B Ⅱ to LC3B Ⅰ, Beclin 1, P62, AMPK, mTOR, P70S6K, actin, and phosphorylation of AMPK, mTOR, P70S6K were determined by western blotting. Moreover, a nude murine node with transplanted NC-dsRNA or NIS-482-transfected SW579 cells was used to examine the effect of NIS-mediated autophagy in vivo. And the levels of caspase 3 and ki67 were examined by immunohistochemical staining assay. RESULTS saRNA mediated NIS mRNA and protein upregulated in SW579 cells. saRNA-mediated NIS expression inhibited cell proliferation, induced apoptosis and autophagy, and promoted iodide uptake in SW579 cells. Moreover, the effects of NIS on cells were enhanced by autophagy activator Rapamycin whereas reversed by autophagy inhibitor 3-Methyladenine (3-MA). For mechanism analysis, we found that NIS upregulation exerted the effects on cell proliferation, apoptosis, autophagy, and iodide uptake via regulating AMPK/mTOR pathway. We also demonstrated that saRNA-mediated NIS expression promoted iodide uptake in vivo. CONCLUSION saRNA-mediated NIS expression acted as a critical role in increasing iodide uptake via AMPK/mTOR pathway in thyroid cancer.
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Talap J, Zhao J, Shen M, Song Z, Zhou H, Kang Y, Sun L, Yu L, Zeng S, Cai S. Recent advances in therapeutic nucleic acids and their analytical methods. J Pharm Biomed Anal 2021; 206:114368. [PMID: 34571322 DOI: 10.1016/j.jpba.2021.114368] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022]
Abstract
Therapeutic nucleic acids are various chemically modified RNA or DNA with different functions, which mainly play roles at the gene level. Owing to its accurately targeting at pathogenic genes, nucleic acid based therapeutics have a wide range of application prospects. Recently, the improvement on chemical synthesis and delivery materials accelerated the development of therapeutic nucleic acids rapidly. Up to now, 17 nucleic acid based therapeutics approved by Food and Drug Administration (FDA) or European Medicines Agency (EMA). The development of therapeutics raised higher requirements for analytical methods, both in quality control and in clinical research. The first part of this review introduces different classes of therapeutic nucleic acids, including antisense oligonucleotide (ASO), RNA interference (RNAi) therapy, mRNA, aptamer and other classes which are under research. The second part reviews the therapeutic nucleic acids commercialized from 2019 to now. The third part discusses the analytical methods for nucleic acid based therapeutics, including liquid chromatography-based methods, capillary gel electrophoresis (CGE), hybridization enzyme-linked immunosorbent assay (ELISA) and other infrequently used methods. Finally, the advantages and shortcomings of these methods are summarized, and the future development of analysis methods are prospected.
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Affiliation(s)
- Jadera Talap
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Jing Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
| | - Minzhe Shen
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zihan Song
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Hui Zhou
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yu Kang
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Lianli Sun
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Lushan Yu
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Su Zeng
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Cancer Center of Zhejiang University, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, China.
| | - Sheng Cai
- Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Cancer Center of Zhejiang University, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, China.
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Tan CP, Sinigaglia L, Gomez V, Nicholls J, Habib NA. RNA Activation-A Novel Approach to Therapeutically Upregulate Gene Transcription. Molecules 2021; 26:molecules26216530. [PMID: 34770939 PMCID: PMC8586927 DOI: 10.3390/molecules26216530] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/23/2021] [Accepted: 10/26/2021] [Indexed: 12/12/2022] Open
Abstract
RNA activation (RNAa) is a mechanism whereby RNA oligos complementary to genomic sequences around the promoter region of genes increase the transcription output of their target gene. Small activating RNA (saRNA) mediate RNAa through interaction with protein co-factors to facilitate RNA polymerase II activity and nucleosome remodeling. As saRNA are small, versatile and safe, they represent a new class of therapeutics that can rescue the downregulation of critical genes in disease settings. This review highlights our current understanding of saRNA biology and describes various examples of how saRNA are successfully used to treat various oncological, neurological and monogenic diseases. MTL-CEBPA, a first-in-class compound that reverses CEBPA downregulation in oncogenic processes using CEBPA-51 saRNA has entered clinical trial for the treatment of hepatocellular carcinoma (HCC). Preclinical models demonstrate that MTL-CEBPA reverses the immunosuppressive effects of myeloid cells and allows for the synergistic enhancement of other anticancer drugs. Encouraging results led to the initiation of a clinical trial combining MTL-CEBPA with a PD-1 inhibitor for treatment of solid tumors.
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Affiliation(s)
- Choon Ping Tan
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
| | - Laura Sinigaglia
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
| | - Valentí Gomez
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
| | - Joanna Nicholls
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
| | - Nagy A. Habib
- MiNA Therapeutics Ltd., Translation & Innovation Hub, 84 Wood Lane, London W12 0BZ, UK; (C.P.T.); (L.S.); (V.G.); (J.N.)
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London W12 0NN, UK
- Correspondence: ; Tel.: +44-(0)20-3313-8574
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Weuring W, Geerligs J, Koeleman BPC. Gene Therapies for Monogenic Autism Spectrum Disorders. Genes (Basel) 2021; 12:genes12111667. [PMID: 34828273 PMCID: PMC8617899 DOI: 10.3390/genes12111667] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/20/2021] [Accepted: 10/21/2021] [Indexed: 12/26/2022] Open
Abstract
Novel genome editing and transient gene therapies have been developed the past ten years, resulting in the first in-human clinical trials for monogenic disorders. Syndromic autism spectrum disorders can be caused by mutations in a single gene. Given the monogenic aspect and severity of syndromic ASD, it is an ideal candidate for gene therapies. Here, we selected 11 monogenic ASD syndromes, validated by animal models, and reviewed current gene therapies for each syndrome. Given the wide variety and novelty of some forms of gene therapy, the best possible option must be decided based on the gene and mutation.
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miR-2337 induces TGF-β1 production in granulosa cells by acting as an endogenous small activating RNA. Cell Death Discov 2021; 7:253. [PMID: 34537818 PMCID: PMC8449777 DOI: 10.1038/s41420-021-00644-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/16/2021] [Accepted: 09/07/2021] [Indexed: 01/17/2023] Open
Abstract
Transforming growth factor-β1 (TGF-β1) is essential for ovarian function and female fertility in mammals. Herein, we identified three completely linked variants, including two known variants referred to as c.1583A > G and c.1587A > G and the novel variant c.2074A > C in the porcine TGF-β1 3′-UTR. An important role of these variants in Yorkshire sow fertility was revealed. Variants c.1583A > G and c.1587A > G were located at the miRNA response element (MRE) of miR-2337 and affected miR-2337 regulation of TGF-β1 3′-UTR activity. Interestingly, miR-2337 induces, not reduces the transcription and production of TGF-β1 in granulosa cells (GCs). Mechanistically, miR-2337 enhances TGF-β1 promoter activity via the MRE motif in the core promoter region and alters histone modifications, including H3K4me2, H3K4me3, H3K9me2, and H3K9ac. In addition, miR-2337 controls TGF-β1-mediated activity of the TGF-β signaling pathway and GC apoptosis. Taken together, our findings identify miR-2337 as an endogenous small activating RNA (saRNA) of TGF-β1 in GCs, while miR-2337 is identified as a small activator of the TGF-β signaling pathway which is expected to be a new target for rescuing GC apoptosis and treating low fertility.
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40
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Industry news update covering May 2021. Ther Deliv 2021. [DOI: 10.4155/tde-2021-0047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Yu AM, Tu MJ. Deliver the promise: RNAs as a new class of molecular entities for therapy and vaccination. Pharmacol Ther 2021; 230:107967. [PMID: 34403681 PMCID: PMC9477512 DOI: 10.1016/j.pharmthera.2021.107967] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/06/2021] [Accepted: 07/13/2021] [Indexed: 12/19/2022]
Abstract
The concepts of developing RNAs as new molecular entities for therapies have arisen again and again since the discoveries of antisense RNAs, direct RNA-protein interactions, functional noncoding RNAs, and RNA-directed gene editing. The feasibility was demonstrated with the development and utilization of synthetic RNA agents to selectively control target gene expression, modulate protein functions or alter the genome to manage diseases. Rather, RNAs are labile to degradation and cannot cross cell membrane barriers, making it hard to develop RNA medications. With the development of viable RNA technologies, such as chemistry and pharmaceutics, eight antisense oligonucleotides (ASOs) (fomivirsen, mipomersen, eteplirsen, nusinersen, inotersen, golodirsen, viltolarsen and casimersen), one aptamer (pegaptanib), and three small interfering RNAs (siRNAs) (patisiran, givosiran and lumasiran) have been approved by the United States Food and Drug Administration (FDA) for therapies, and two mRNA vaccines (BNT162b2 and mRNA-1273) under Emergency Use Authorization for the prevention of COVID-19. Therefore, RNAs have become a great addition to small molecules, proteins/antibodies, and cell-based modalities to improve the public health. In this article, we first summarize the general characteristics of therapeutic RNA agents, including chemistry, common delivery strategies, mechanisms of actions, and safety. By overviewing individual RNA medications and vaccines approved by the FDA and some agents under development, we illustrate the unique compositions and pharmacological actions of RNA products. A new era of RNA research and development will likely lead to commercialization of more RNA agents for medical use, expanding the range of therapeutic targets and increasing the diversity of molecular modalities.
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Affiliation(s)
- Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA.
| | - Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, CA 95817, USA
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Shigdar S, Schrand B, Giangrande PH, de Franciscis V. Aptamers: Cutting edge of cancer therapies. Mol Ther 2021; 29:2396-2411. [PMID: 34146729 PMCID: PMC8353241 DOI: 10.1016/j.ymthe.2021.06.010] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 06/06/2021] [Accepted: 06/09/2021] [Indexed: 02/07/2023] Open
Abstract
The development of an aptamer-based therapeutic has rapidly progressed following the first two reports in the 1990s, underscoring the advantages of aptamer drugs associated with their unique binding properties. In 2004, the US Food and Drug Administration (FDA) approved the first therapeutic aptamer for the treatment of neovascular age-related macular degeneration, Macugen developed by NeXstar. Since then, eleven aptamers have successfully entered clinical trials for various therapeutic indications. Despite some of the pre-clinical and clinical successes of aptamers as therapeutics, no aptamer has been approved by the FDA for the treatment of cancer. This review highlights the most recent and cutting-edge approaches in the development of aptamers for the treatment of cancer types most refractory to conventional therapies. Herein, we will review (1) the development of aptamers to enhance anti-cancer immunity and as delivery tools for inducing the expression of immunogenic neoantigens; (2) the development of the most promising therapeutic aptamers designed to target the hard-to-treat cancers such as brain tumors; and (3) the development of "carrier" aptamers able to target and penetrate tumors and metastasis, delivering RNA therapeutics to the cytosol and nucleus.
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Affiliation(s)
- Sarah Shigdar
- School of Medicine and Centre for Molecular and Medical Research, Deakin University, 75 Pigdons Road, Waurn Ponds, VIC 3216, Australia
| | - Brett Schrand
- TCR(2) Therapeutics, Inc., 100 Binney Street, Cambridge, MA 02142, USA
| | - Paloma H Giangrande
- Internal Medicine, University of Iowa, Iowa City, IA 52242, USA; VP Platform Discovery Sciences, Biology, Wave Life Sciences, Cambridge, MA 02138, USA
| | - Vittorio de Franciscis
- Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy; Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA.
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Barabino SML, Citterio E, Ronchi AE. Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia. Cancers (Basel) 2021; 13:cancers13153753. [PMID: 34359655 PMCID: PMC8345071 DOI: 10.3390/cancers13153753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary The advent of DNA massive sequencing technologies has allowed for the first time an extensive look into the heterogeneous spectrum of genes and mutations underpinning myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). In this review, we wish to explore the most recent advances and the rationale for the potential therapeutic interest of three main actors in myelo-leukemic transformation: transcription factors that govern myeloid differentiation; RNA splicing factors, which ensure proper mRNA maturation and whose mutations increase R-loops formation; and deubiquitinating enzymes, which contribute to genome stability in hematopoietic stem cells (HSCs). Abstract Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.
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Tanwar VS, Reddy MA, Natarajan R. Emerging Role of Long Non-Coding RNAs in Diabetic Vascular Complications. Front Endocrinol (Lausanne) 2021; 12:665811. [PMID: 34234740 PMCID: PMC8255808 DOI: 10.3389/fendo.2021.665811] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 06/01/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic metabolic disorders such as obesity and diabetes are associated with accelerated rates of macrovascular and microvascular complications, which are leading causes of morbidity and mortality worldwide. Further understanding of the underlying molecular mechanisms can aid in the development of novel drug targets and therapies to manage these disorders more effectively. Long non-coding RNAs (lncRNAs) that do not have protein-coding potential are expressed in a tissue- and species-specific manner and regulate diverse biological processes. LncRNAs regulate gene expression in cis or in trans through various mechanisms, including interaction with chromatin-modifying proteins and other regulatory proteins and via posttranscriptional mechanisms, including acting as microRNA sponges or as host genes of microRNAs. Emerging evidence suggests that major pathological factors associated with diabetes such as high glucose, free fatty acids, proinflammatory cytokines, and growth factors can dysregulate lncRNAs in inflammatory, cardiac, vascular, and renal cells leading to altered expression of key inflammatory genes and fibrotic genes associated with diabetic vascular complications. Here we review recent reports on lncRNA characterization, functions, and mechanisms of action in diabetic vascular complications and translational approaches to target them. These advances can provide new insights into the lncRNA-dependent actions and mechanisms underlying diabetic vascular complications and uncover novel lncRNA-based biomarkers and therapies to reduce disease burden and mortality.
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Affiliation(s)
| | | | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, United States
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Tseng CC, Wong MC, Liao WT, Chen CJ, Lee SC, Yen JH, Chang SJ. Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases. Int J Mol Sci 2021; 22:ijms22084187. [PMID: 33919522 PMCID: PMC8073710 DOI: 10.3390/ijms22084187] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022] Open
Abstract
Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients.
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Affiliation(s)
- Chia-Chun Tseng
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (J.-H.Y.)
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
| | - Man-Chun Wong
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Wei-Ting Liao
- Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- Correspondence: (W.-T.L.); (S.-J.C.); Tel.: +886-7-3121101 (W.-T.L.); +886-7-5916679 (S.-J.C.); Fax:+886-7-3125339 (W.-T.L.); +886-7-5919264 (S.-J.C.)
| | - Chung-Jen Chen
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan;
| | - Su-Chen Lee
- Laboratory Diagnosis of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Jeng-Hsien Yen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-C.T.); (J.-H.Y.)
- Division of Rheumatology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Biological Science and Technology, National Chiao-Tung University, Hsinchu 30010, Taiwan
| | - Shun-Jen Chang
- Department of Kinesiology, Health and Leisure Studies, National University of Kaohsiung, Kaohsiung 81148, Taiwan
- Correspondence: (W.-T.L.); (S.-J.C.); Tel.: +886-7-3121101 (W.-T.L.); +886-7-5916679 (S.-J.C.); Fax:+886-7-3125339 (W.-T.L.); +886-7-5919264 (S.-J.C.)
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Oligonucleotide-Based Therapies for Renal Diseases. Biomedicines 2021; 9:biomedicines9030303. [PMID: 33809425 PMCID: PMC8001091 DOI: 10.3390/biomedicines9030303] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/09/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023] Open
Abstract
The global burden of chronic kidney disease (CKD) is increasing every year and represents a great cost for public healthcare systems, as the majority of these diseases are progressive. Therefore, there is an urgent need to develop new therapies. Oligonucleotide-based drugs are emerging as novel and promising alternatives to traditional drugs. Their expansion corresponds with new knowledge regarding the molecular basis underlying CKD, and they are already showing encouraging preclinical results, with two candidates being evaluated in clinical trials. However, despite recent technological advances, efficient kidney delivery remains challenging, and the presence of off-targets and side-effects precludes development and translation to the clinic. In this review, we provide an overview of the various oligotherapeutic strategies used preclinically, emphasizing the most recent findings in the field, together with the different strategies employed to achieve proper kidney delivery. The use of different nanotechnological platforms, including nanocarriers, nanoparticles, viral vectors or aptamers, and their potential for the development of more specific and effective treatments is also outlined.
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Jiang W, Zhu D, Wang C, Zhu Y. Tumor suppressing effects of tristetraprolin and its small double-stranded RNAs in bladder cancer. Cancer Med 2021; 10:269-285. [PMID: 33259133 PMCID: PMC7826468 DOI: 10.1002/cam4.3622] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 10/20/2020] [Accepted: 10/25/2020] [Indexed: 12/23/2022] Open
Abstract
Bladder cancer (BCa) is a common malignant tumor of urinary system with few treatments, so more useful therapeutic targets are still needed. Antitumor effects of tristetraprolin (TTP) have been explored in many type tumors, but its roles in bladder cancer are still unknown until now. In this study, public expression profiles and tissue microarray analysis showed that TTP mRNA and protein levels decreased in BCa relative to the normal bladder tissue. To explore biological functions of TTP in BCa, 488 TTP target genes, which could be both suppressed and bound by TTP, were identified by comprehensively analyzing publicly available high-throughput data obtained from Gene Expression Omnibus (GEO). Gene enrichment analysis showed that these genes were enriched in pathways such as cell cycle, epithelial to mesenchymal transition (EMT), and Wnt signaling. Clustering analysis and gene set variation analysis indicated that patients with high expression of TTP target genes had poorer prognosis and stronger tumor proliferation ability relative to the BCa patients with low expression of TTP target genes. In vitro experiments validated that TTP could suppress proliferation, migration, and invasiveness of BCa cells. And TTP could suppress mRNA expression of cyclin-dependent kinase 1 (CDK1) in BCa cells by target its 3' UTR. Then, we identified a new small double-stranded RNA (dsRNA) named dsTTP-973 which could increase TTP expression in BCa cells, in vivo and in vitro experiments revealed that dsTTP-973 could suppress aggressiveness of BCa. In conclusion, TTP played a role of tumor suppressor gene in BCa like other tumors, and its dsRNA named dsTTP-973 could induce TTP expression in BCa and suppress aggressiveness of BCa. With the help of materials science, dsTTP-973 may become a potential treatment for BCa in the future.
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Affiliation(s)
- Wen Jiang
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Dandan Zhu
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chenghe Wang
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yu Zhu
- Department of UrologyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
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Dammes N, Peer D. Paving the Road for RNA Therapeutics. Trends Pharmacol Sci 2020; 41:755-775. [PMID: 32893005 PMCID: PMC7470715 DOI: 10.1016/j.tips.2020.08.004] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 08/06/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022]
Abstract
Therapeutic RNA molecules possess high potential for treating medical conditions if they can successfully reach the target cell upon administration. However, unmodified RNA molecules are rapidly degraded and cleared from the circulation. In addition, their large size and negative charge complicates their passing through the cell membrane. The difficulty of RNA therapy, therefore, lies in the efficient intracellular delivery of intact RNA molecules to the tissue of interest without inducing adverse effects. Here, we outline the recent developments in therapeutic RNA delivery and discuss the wide potential in manipulating the function of cells with RNAs. The focus is not only on the variety of delivery strategies but also on the versatile nature of RNA and its wide applicability. This wide applicability is especially interesting when considering the modular nature of nucleic acids. An optimal delivery vehicle, therefore, can facilitate numerous clinical applications of RNA.
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Affiliation(s)
- Niels Dammes
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv 69978, Israel,School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel,Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel,Center for Nanoscience and Nanotechnology, and Tel Aviv University, Tel Aviv 69978, Israel,Cancer Biology Research Center, Tel Aviv University, Tel Aviv 69978, Israel
| | - Dan Peer
- Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv 69978, Israel; School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel; Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel; Center for Nanoscience and Nanotechnology, and Tel Aviv University, Tel Aviv 69978, Israel; Cancer Biology Research Center, Tel Aviv University, Tel Aviv 69978, Israel.
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Zhou LY, Qin Z, Zhu YH, He ZY, Xu T. Current RNA-based Therapeutics in Clinical Trials. Curr Gene Ther 2020; 19:172-196. [PMID: 31566126 DOI: 10.2174/1566523219666190719100526] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/26/2019] [Accepted: 07/09/2019] [Indexed: 02/08/2023]
Abstract
Long-term research on various types of RNAs has led to further understanding of diverse mechanisms, which eventually resulted in the rapid development of RNA-based therapeutics as powerful tools in clinical disease treatment. Some of the developing RNA drugs obey the antisense mechanisms including antisense oligonucleotides, small interfering RNAs, microRNAs, small activating RNAs, and ribozymes. These types of RNAs could be utilized to inhibit/activate gene expression or change splicing to provide functional proteins. In the meantime, some others based on different mechanisms like modified messenger RNAs could replace the dysfunctional endogenous genes to manage some genetic diseases, and aptamers with special three-dimensional structures could bind to specific targets in a high-affinity manner. In addition, the recent most popular CRISPR-Cas technology, consisting of a crucial single guide RNA, could edit DNA directly to generate therapeutic effects. The desired results from recent clinical trials indicated the great potential of RNA-based drugs in the treatment of various diseases, but further studies on improving delivery materials and RNA modifications are required for the novel RNA-based drugs to translate to the clinic. This review focused on the advances and clinical studies of current RNA-based therapeutics, analyzed their challenges and prospects.
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Affiliation(s)
- Ling-Yan Zhou
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Zhou Qin
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
| | - Yang-Hui Zhu
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.,State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Zhi-Yao He
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China.,State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Ting Xu
- Department of Pharmacy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan 610041, China
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Abstract
Cancer immunotherapy has shown great potential as witnessed by an increasing number of immuno-oncology drug approvals in the past few years. Meanwhile, the field of nucleic acid therapeutics has made significant advancement. Nucleic acid therapeutics, such as plasmids, antisense oligonucleotides (ASO), small interfering RNA (siRNA) and microRNA, messenger RNA (mRNA), immunomodulatory DNA/RNA, and gene-editing guide RNA (gRNA) are attractive due to their versatile abilities to alter the expression of target endogenous genes or even synthetic genes, and modulate the immune responses. These abilities can play vital roles in the development of novel immunotherapy strategies. However, limited by the intrinsic physicochemical properties such as negative charges, hydrophilicity, as well as susceptibility to enzymatic degradation, the delivery of nucleic acid therapeutics faces multiple challenges. It is therefore pivotal to develop drug delivery systems that can carry, protect, and specifically deliver and release nucleic acid therapeutics to target tissues and cells. In this review, we attempted to summarize recent advances in nucleic acid therapeutics and the delivery systems for these therapeutics in cancer immunotherapy.
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Affiliation(s)
- Shurong Zhou
- Department of Pharmaceutics, Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology, Drug Discovery and Development (ISB3D), School of Pharmacy, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23219, USA
| | - Wenjie Chen
- Department of Pharmaceutics, Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology, Drug Discovery and Development (ISB3D), School of Pharmacy, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23219, USA
| | - Janet Cole
- Department of Pharmaceutics, Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology, Drug Discovery and Development (ISB3D), School of Pharmacy, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23219, USA
| | - Guizhi Zhu
- Department of Pharmaceutics, Center for Pharmaceutical Engineering and Sciences, Institute for Structural Biology, Drug Discovery and Development (ISB3D), School of Pharmacy, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23219, USA
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