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Xia B, Zhu Q. Aptamer-ODN Chimeras: Enabling Cell-Specific ODN Targeting Therapy. Cells 2025; 14:697. [PMID: 40422200 DOI: 10.3390/cells14100697] [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: 03/13/2025] [Revised: 04/23/2025] [Accepted: 05/10/2025] [Indexed: 05/28/2025] Open
Abstract
Oligonucleotides (ODNs) such as siRNA, saRNA, and miRNA regulate gene expression through a variety of molecular mechanisms and show unique potential in the treatment of genetic diseases and rare diseases, but their clinical application is still limited by the efficiency of the delivery system, especially the problem of the insufficient targeting of extrahepatic tissues. As homologous nucleic acid molecules, aptamers have become a key tool to improve the targeted delivery of ODNs. Aptamer-ODN chimeras can not only bind to multiple proteins on the cell surface with high specificity and selectivity, but they can also internalize into cells. Furthermore, they outperform traditional delivery systems in terms of cost-effectiveness and chemical modification flexibility. This review systematically summarizes the origin and progress of aptamer-ODN chimera therapy, discusses some innovative design strategies, and proposes views on the future direction of aptamer-ODN chimeras.
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Affiliation(s)
- Bei Xia
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Qubo Zhu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
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2
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Liu M, Wang Y, Zhang Y, Hu D, Tang L, Zhou B, Yang L. Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines. Signal Transduct Target Ther 2025; 10:73. [PMID: 40059188 PMCID: PMC11891339 DOI: 10.1038/s41392-024-02112-8] [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: 07/17/2024] [Revised: 10/23/2024] [Accepted: 12/13/2024] [Indexed: 03/17/2025] Open
Abstract
The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored. Compared with conventional treatments, small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing. As a result of recent technological advances, efficient small nucleic acid delivery for therapeutic and biomedical applications has been achieved, accelerating their clinical translation. Here, we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms. We also discuss the key advances in the design, development and therapeutic application of each delivery platform. Furthermore, this review presents comprehensive profiles of currently approved small nucleic acid drugs, including 11 antisense oligonucleotides (ASOs), 2 aptamers and 6 siRNA drugs, summarizing their modifications, disease-specific mechanisms of action and delivery strategies. Other candidates whose clinical trial status has been recorded and updated are also discussed. We also consider strategic issues such as important safety considerations, novel vectors and hurdles for translating academic breakthroughs to the clinic. Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously "undruggable" targets, suggesting that they could be useful for guiding the development of additional clinical candidates.
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Affiliation(s)
- Mohan Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yusi Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yibing Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Die Hu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Bailing Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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DeFranciscis V, Amabile G, Kortylewski M. Clinical applications of oligonucleotides for cancer therapy. Mol Ther 2025:S1525-0016(25)00172-8. [PMID: 40045578 DOI: 10.1016/j.ymthe.2025.02.045] [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: 12/15/2024] [Revised: 02/21/2025] [Accepted: 02/28/2025] [Indexed: 03/17/2025] Open
Abstract
Oligonucleotide therapeutics (ONTs) represent a rapidly evolving modality for cancer treatment, capitalizing on their ability to modulate gene expression with high specificity. With more than 20 nucleic acid-based therapies that gained regulatory approval, advances in chemical modifications, sequence optimization, and novel delivery systems have propelled ONTs from research tools to clinical realities. ONTs, including siRNAs, antisense oligonucleotides, saRNA, miRNA, aptamers, and decoys, offer promising solutions for targeting previously "undruggable" molecules, such as transcription factors, and enhancing cancer immunotherapy by overcoming tumor immune evasion. The promise of ONT application in cancer treatment is exemplified by the recent FDA approval of the first oligonucleotide-based treatment to myeloproliferative disease. At the same time, there are challenges in delivering ONTs to specific tissues, mitigating off-target effects, and improving cellular uptake and endosomal release. This review provides a comprehensive overview of ONTs in clinical trials, emerging delivery strategies, and innovative therapeutic approaches, emphasizing the role of ONTs in immunotherapy and addressing hurdles that hinder their clinical translation. By examining advances and remaining challenges, we highlight opportunities for ONTs to revolutionize oncology and enhance patient outcomes.
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Affiliation(s)
- Vittorio DeFranciscis
- National Research Council, Institute of Genetic and Biomedical Research, Milan, Italy
| | | | - Marcin Kortylewski
- Department of Immuno-Oncology, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USA.
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Hussain M, Qi Z, Asgari S. Interaction of the Wolbachia surface protein with a novel pro-viral protein from Aedes aegypti. mBio 2025; 16:e0148624. [PMID: 39576110 PMCID: PMC11708058 DOI: 10.1128/mbio.01486-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 10/31/2024] [Indexed: 01/11/2025] Open
Abstract
Dengue virus (DENV) and other flaviviruses are prevented from replicating in mosquitoes by Wolbachia. To date, several reports have appeared that highlight multiple molecular and cellular pathways involved in the blocking mechanism, which underlines the complicated nature of the mechanism. Here, we developed a hypothesis on whether Wolbachia proteins interact with pro-viral host proteins by using a unique approach to study the antiviral mechanism based on Wolbachia-host protein-protein interaction. We selected Wolbachia surface protein (WSP) for co-immunoprecipitation because of its abundance and possible secretion. We first confirmed WSP's secretion in mosquito cells and found two host proteins, Ae. aegypti serine-threonine kinase (STK) and synaptic vesicle membrane (SVM) protein VAT-1, and one Wolbachia protein (wGroEL) interacting with WSP. We examined the role of STK and SVM genes in relation to DENV replication in Ae. aegypti mosquitoes and mosquito cell lines with and without Wolbachia. In DENV-infected Aag2 cells, the expression of SVM and STK was significantly increased. However, although these genes were induced in Wolbachia-infected Aag2 cells, they were downregulated after DENV infection. Silencing of STK, but not SVM, reduced DENV replication in Aag2 cells and mosquitoes. Conversely, RNA activation of STK, by utilizing promoter induction via short activating oligos, resulted in higher DENV replication in Wolbachia-infected and uninfected cell lines. Overall, our findings suggest that STK is a pro-viral gene, and Wolbachia WSP binds to STK, possibly making it less accessible for DENV replication. IMPORTANCE Wolbachia is an endosymbiotic bacterium that blocks the replication of arboviruses in transinfected Aedes aegypti mosquitoes. In this study, we focused on identifying the potential interaction of Wolbachia proteins with the host pro-viral proteins. For this, we embarked on identifying the interacting proteins with a major Wolbachia protein, WSP, which is both structural and also secreted into the host cells. An Ae. aegypti STK was identified, which is induced in DENV and Wolbachia-infected cells. Silencing or induction of the gene led to reduced and increased DENV replication in vitro. Consistently, knocking down the gene in mosquitoes resulted in decreased virus replication. We hypothesize that WSP may sequester STK, which is pro-viral, contributing to Wolbachia virus blocking.
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Affiliation(s)
- Mazhar Hussain
- Australian Infectious Disease Research Centre, School of Biological Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Zhi Qi
- Australian Infectious Disease Research Centre, School of Biological Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Sassan Asgari
- Australian Infectious Disease Research Centre, School of Biological Sciences, The University of Queensland, Brisbane, Queensland, Australia
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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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Yuan Y, Sun W, Xie J, Zhang Z, Luo J, Han X, Xiong Y, Yang Y, Zhang Y. RNA nanotherapeutics for hepatocellular carcinoma treatment. Theranostics 2025; 15:965-992. [PMID: 39776807 PMCID: PMC11700867 DOI: 10.7150/thno.102964] [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: 08/29/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, particularly due to the limited effectiveness of current therapeutic options for advanced-stage disease. The efficacy of traditional treatments is often compromised by the intricate liver microenvironment and the inherent heterogeneity. RNA-based therapeutics offer a promising alternative, utilizing the innovative approach of targeting aberrant molecular pathways and modulating the tumor microenvironment. The integration of nanotechnology in this field, through the development of advanced nanocarrier delivery systems, especially lipid nanoparticles (LNPs), polymer nanoparticles (PNPs), and bioinspired vectors, enhances the precision and efficacy of RNA therapies. This review highlights the significant progress in RNA nanotherapeutics for HCC treatment, covering micro RNA (miRNA), small interfering RNA (siRNA), message RNA (mRNA), and small activating RNA (saRNA) mediated gene silencing, therapeutic protein restoration, gene activation, cancer vaccines, and concurrent therapy. It further comprehensively discusses the prevailing challenges within this therapeutic landscape and provides a forward-looking perspective on the potential of RNA nanotherapeutics to transform HCC treatment.
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Affiliation(s)
- Yihang Yuan
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
- Department of General Surgery Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School Nanjing University, Nanjing 210008, China
| | - Weijie Sun
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China
| | - Jiaqi Xie
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
| | - Ziheng Zhang
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Jing Luo
- Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Xiangfei Han
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Yongfu Xiong
- Department of Hepatobiliary Surgery, Academician (Expert) Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong 637600, China
| | - Yang Yang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
| | - Yang Zhang
- Center for Nanomedicine and Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Li X, Huang Z, Bai J, Che A, Zhou J, Yang H. Molecular profiling unveils pyroptosis markers in preterm birth. FASEB J 2024; 38:e70112. [PMID: 39673596 DOI: 10.1096/fj.202302716rr] [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: 12/31/2023] [Revised: 08/29/2024] [Accepted: 10/04/2024] [Indexed: 12/16/2024]
Abstract
Through a comprehensive examination of pyroptosis-related differential expressed genes (PRDEGs), this work investigates the molecular complexities of spontaneous preterm birth (SPTB), also known as premature delivery, before the due date. Through the process of merging and correcting batch effects in the GSE120480 and GSE73714 datasets, we were able to identify 36 PRDEGs that exhibited significant expression differentiation in SPTB. Through functional enrichment and pathway analysis, their importance in amino acid transport and cytokine receptor interaction has been highlighted. Among the genes that have emerged as crucial, CEBPA, APOA1, and CEP55 have been identified. The relevance of these molecules was demonstrated using experimental knockdowns, which also suggested that they could be used as molecular biomarkers and therapeutic targets for SPTB.
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Affiliation(s)
- Xiaoyun Li
- Department of Ultrasound Medicine, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, China
| | - Zhulan Huang
- Department of Ultrasound Medicine, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, China
| | - Jiangtao Bai
- Central Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, China
| | - Aiwen Che
- Department of Pathology, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, China
| | - Jinhua Zhou
- Department of Obstetrics, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, China
| | - Hongmei Yang
- Department of Clinical Laboratory, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, China
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Sun X, Setrerrahmane S, Li C, Hu J, Xu H. Nucleic acid drugs: recent progress and future perspectives. Signal Transduct Target Ther 2024; 9:316. [PMID: 39609384 PMCID: PMC11604671 DOI: 10.1038/s41392-024-02035-4] [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: 10/31/2023] [Revised: 09/20/2024] [Accepted: 10/25/2024] [Indexed: 11/30/2024] Open
Abstract
High efficacy, selectivity and cellular targeting of therapeutic agents has been an active area of investigation for decades. Currently, most clinically approved therapeutics are small molecules or protein/antibody biologics. Targeted action of small molecule drugs remains a challenge in medicine. In addition, many diseases are considered 'undruggable' using standard biomacromolecules. Many of these challenges however, can be addressed using nucleic therapeutics. Nucleic acid drugs (NADs) are a new generation of gene-editing modalities characterized by their high efficiency and rapid development, which have become an active research topic in new drug development field. However, many factors, including their low stability, short half-life, high immunogenicity, tissue targeting, cellular uptake, and endosomal escape, hamper the delivery and clinical application of NADs. Scientists have used chemical modification techniques to improve the physicochemical properties of NADs. In contrast, modified NADs typically require carriers to enter target cells and reach specific intracellular locations. Multiple delivery approaches have been developed to effectively improve intracellular delivery and the in vivo bioavailability of NADs. Several NADs have entered the clinical trial recently, and some have been approved for therapeutic use in different fields. This review summarizes NADs development and evolution and introduces NADs classifications and general delivery strategies, highlighting their success in clinical applications. Additionally, this review discusses the limitations and potential future applications of NADs as gene therapy candidates.
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Affiliation(s)
- Xiaoyi Sun
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | | | - Chencheng Li
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Jialiang Hu
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China
| | - Hanmei Xu
- Jiangsu Province Engineering Research Center of Synthetic Peptide Drug Discovery and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
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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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10
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Kovecses O, Mercier FE, McKeague M. Nucleic acid therapeutics as differentiation agents for myeloid leukemias. Leukemia 2024; 38:1441-1454. [PMID: 38424137 PMCID: PMC11216999 DOI: 10.1038/s41375-024-02191-0] [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: 09/09/2023] [Revised: 02/15/2024] [Accepted: 02/19/2024] [Indexed: 03/02/2024]
Abstract
Differentiation therapy has proven to be a success story for patients with acute promyelocytic leukemia. However, the remaining subtypes of acute myeloid leukemia (AML) are treated with cytotoxic chemotherapies that have limited efficacy and a high likelihood of resistance. As differentiation arrest is a hallmark of AML, there is increased interest in developing differentiation-inducing agents to enhance disease-free survival. Here, we provide a comprehensive review of current reports and future avenues of nucleic acid therapeutics for AML, focusing on the use of targeted nucleic acid drugs to promote differentiation. Specifically, we compare and discuss the precision of small interfering RNA, small activating RNA, antisense oligonucleotides, and aptamers to modulate gene expression patterns that drive leukemic cell differentiation. We delve into preclinical and clinical studies that demonstrate the efficacy of nucleic acid-based differentiation therapies to induce leukemic cell maturation and reduce disease burden. By directly influencing the expression of key genes involved in myeloid maturation, nucleic acid therapeutics hold the potential to induce the differentiation of leukemic cells towards a more mature and less aggressive phenotype. Furthermore, we discuss the most critical challenges associated with developing nucleic acid therapeutics for myeloid malignancies. By introducing the progress in the field and identifying future opportunities, we aim to highlight the power of nucleic acid therapeutics in reshaping the landscape of myeloid leukemia treatment.
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MESH Headings
- Humans
- Cell Differentiation/drug effects
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Nucleic Acids/therapeutic use
- Animals
- Leukemia, Myeloid/drug therapy
- Leukemia, Myeloid/genetics
- Leukemia, Myeloid/pathology
- RNA, Small Interfering/genetics
- RNA, Small Interfering/therapeutic use
- Oligonucleotides, Antisense/therapeutic use
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Affiliation(s)
- Olivia Kovecses
- Department of Pharmacology and Therapeutics, McGill University, Montreal, H3G 1Y6, QC, Canada
| | - François E Mercier
- Division of Hematology and Experimental Medicine, Department of Medicine, McGill University, Montreal, H3T 1E2, QC, Canada
| | - Maureen McKeague
- Department of Pharmacology and Therapeutics, McGill University, Montreal, H3G 1Y6, QC, Canada.
- Department of Chemistry, McGill University, Montreal, H3A 0B8, QC, Canada.
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11
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Yuan W, Shi X, Lee LTO. RNA therapeutics in targeting G protein-coupled receptors: Recent advances and challenges. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102195. [PMID: 38741614 PMCID: PMC11089380 DOI: 10.1016/j.omtn.2024.102195] [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: 05/16/2024]
Abstract
G protein-coupled receptors (GPCRs) are the major targets of existing drugs for a plethora of human diseases and dominate the pharmaceutical market. However, over 50% of the GPCRs remain undruggable. To pursue a breakthrough and overcome this situation, there is significant clinical research for developing RNA-based drugs specifically targeting GPCRs, but none has been approved so far. RNA therapeutics represent a unique and promising approach to selectively targeting previously undruggable targets, including undruggable GPCRs. However, the development of RNA therapeutics faces significant challenges in areas of RNA stability and efficient in vivo delivery. This review presents an overview of the advances in RNA therapeutics and the diverse types of nanoparticle RNA delivery systems. It also describes the potential applications of GPCR-targeted RNA drugs for various human diseases.
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Affiliation(s)
- Wanjun Yuan
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau, China
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, People’s Republic of China
| | - Leo Tsz On Lee
- Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa 999078, Macau, China
- Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Taipa 999078, Macau, China
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12
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Yao S, Kasargod A, Chiu R, Torgerson TR, Kupiec-Weglinski JW, Dery KJ. The Coming Age of Antisense Oligos for the Treatment of Hepatic Ischemia/Reperfusion (IRI) and Other Liver Disorders: Role of Oxidative Stress and Potential Antioxidant Effect. Antioxidants (Basel) 2024; 13:678. [PMID: 38929116 PMCID: PMC11200799 DOI: 10.3390/antiox13060678] [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: 04/06/2024] [Revised: 05/21/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
Imbalances in the redox state of the liver arise during metabolic processes, inflammatory injuries, and proliferative liver disorders. Acute exposure to intracellular reactive oxygen species (ROS) results from high levels of oxidative stress (OxS) that occur in response to hepatic ischemia/reperfusion injury (IRI) and metabolic diseases of the liver. Antisense oligonucleotides (ASOs) are an emerging class of gene expression modulators that target RNA molecules by Watson-Crick binding specificity, leading to RNA degradation, splicing modulation, and/or translation interference. Here, we review ASO inhibitor/activator strategies to modulate transcription and translation that control the expression of enzymes, transcription factors, and intracellular sensors of DNA damage. Several small-interfering RNA (siRNA) drugs with N-acetyl galactosamine moieties for the liver have recently been approved. Preclinical studies using short-activating RNAs (saRNAs), phosphorodiamidate morpholino oligomers (PMOs), and locked nucleic acids (LNAs) are at the forefront of proof-in-concept therapeutics. Future research targeting intracellular OxS-related pathways in the liver may help realize the promise of precision medicine, revolutionizing the customary approach to caring for and treating individuals afflicted with liver-specific conditions.
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Affiliation(s)
| | | | | | | | | | - Kenneth J. Dery
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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13
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Mohanty P, Panda P, Acharya RK, Pande B, Bhaskar LVKS, Verma HK. Emerging perspectives on RNA virus-mediated infections: from pathogenesis to therapeutic interventions. World J Virol 2023; 12:242-255. [PMID: 38187500 PMCID: PMC10768389 DOI: 10.5501/wjv.v12.i5.242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/07/2023] [Accepted: 11/29/2023] [Indexed: 12/25/2023] Open
Abstract
RNA viruses continue to pose significant threats to global public health, necessitating a profound understanding of their pathogenic mechanisms and the development of effective therapeutic interventions. This manuscript provides a comprehensive overview of emerging perspectives on RNA virus-mediated infections, spanning from the intricate intricacies of viral pathogenesis to the forefront of innovative therapeutic strategies. A critical exploration of antiviral drugs sets the stage, highlighting the diverse classes of compounds that target various stages of the viral life cycle, underscoring the ongoing efforts to combat viral infections. Central to this discussion is the exploration of RNA-based therapeutics, with a spotlight on messenger RNA (mRNA)-based approaches that have revolutionized the landscape of antiviral interventions. Furthermore, the manuscript delves into the intricate world of delivery systems, exploring inno-vative technologies designed to enhance the efficiency and safety of mRNA vaccines. By analyzing the challenges and advancements in delivery mechanisms, this review offers a roadmap for future research and development in this critical area. Beyond conventional infectious diseases, the document explores the expanding applications of mRNA vaccines, including their promising roles in cancer immunotherapy and personalized medicine approaches. This manuscript serves as a valuable resource for researchers, clinicians, and policymakers alike, offering a nuanced perspective on RNA virus pathogenesis and the cutting-edge therapeutic interventions. By synthesizing the latest advancements and challenges, this review contributes significantly to the ongoing discourse in the field, driving the development of novel strategies to combat RNA virus-mediated infections effectively.
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Affiliation(s)
- Pratik Mohanty
- Department of Bioscience and Bioengineering, Indian Institute of Technology, Guwahati 781039, Assam, India
| | - Poojarani Panda
- Life Science, National Institute of Technology, Rourkela 769008, Odisha, India
| | - Rakesh Kumar Acharya
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Bilaspur 495009, Chhattisgarh, India
| | - Babita Pande
- Department of Physiology, All India Institute of Medical Science, Raipur 492001, chhattisgarh, India
| | - LVKS Bhaskar
- Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, Bilaspur 495009, Chhattisgarh, India
| | - Henu Kumar Verma
- Lung Health and Immunity, Helmholtz Zentrum Munich, Munich 85764, Bayren, Germany
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Vos EN, Demirbas D, Mangel M, Rubio-Gozalbo ME, Levy HL, Berry GT. The treatment of biochemical genetic diseases: From substrate reduction to nucleic acid therapies. Mol Genet Metab 2023; 140:107693. [PMID: 37716025 DOI: 10.1016/j.ymgme.2023.107693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/29/2023] [Accepted: 08/29/2023] [Indexed: 09/18/2023]
Abstract
Newborn screening (NBS) began a revolution in the management of biochemical genetic diseases, greatly increasing the number of patients for whom dietary therapy would be beneficial in preventing complications in phenylketonuria as well as in a few similar disorders. The advent of next generation sequencing and expansion of NBS have markedly increased the number of biochemical genetic diseases as well as the number of patients identified each year. With the avalanche of new and proposed therapies, a second wave of options for the treatment of biochemical genetic disorders has emerged. These therapies range from simple substrate reduction to enzyme replacement, and now ex vivo gene therapy with autologous cell transplantation. In some instances, it may be optimal to introduce nucleic acid therapy during the prenatal period to avoid fetopathy. However, as with any new therapy, complications may occur. It is important for physicians and other caregivers, along with ethicists, to determine what new therapies might be beneficial to the patient, and which therapies have to be avoided for those individuals who have less severe problems and for which standard treatments are available. The purpose of this review is to discuss the "Standard" treatment plans that have been in place for many years and to identify the newest and upcoming therapies, to assist the physician and other healthcare workers in making the right decisions regarding the initiation of both the "Standard" and new therapies. We have utilized several diseases to illustrate the applications of these different modalities and discussed for which disorders they may be suitable. The future is bright, but optimal care of the patient, including and especially the newborn infant, requires a deep knowledge of the disease process and careful consideration of the necessary treatment plan, not just based on the different genetic defects but also with regards to different variants within a gene itself.
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Affiliation(s)
- E Naomi Vos
- Division of Genetics & Genomics, Boston Children's Hospital; and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States of America; Manton Center for Orphan Disease Research, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States of America.
| | - Didem Demirbas
- Division of Genetics & Genomics, Boston Children's Hospital; and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States of America; Manton Center for Orphan Disease Research, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States of America.
| | - Matthew Mangel
- Division of Genetics & Genomics, Boston Children's Hospital; and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States of America.
| | - M Estela Rubio-Gozalbo
- Department of Pediatrics and Clinical Genetics, Maastricht University Medical Centre+, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands; GROW, Maastricht University, Minderbroedersberg 4-6, 6211 LK Maastricht, the Netherlands; MetabERN: European Reference Network for Hereditary Metabolic Disorders, Udine, Italy; UMD: United for Metabolic Diseases Member, Amsterdam, the Netherlands.
| | - Harvey L Levy
- Division of Genetics & Genomics, Boston Children's Hospital; and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States of America.
| | - Gerard T Berry
- Division of Genetics & Genomics, Boston Children's Hospital; and Department of Pediatrics, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States of America; Manton Center for Orphan Disease Research, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States of America.
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Klipp A, Burger M, Leroux JC. Get out or die trying: Peptide- and protein-based endosomal escape of RNA therapeutics. Adv Drug Deliv Rev 2023; 200:115047. [PMID: 37536508 DOI: 10.1016/j.addr.2023.115047] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 06/28/2023] [Accepted: 08/01/2023] [Indexed: 08/05/2023]
Abstract
RNA therapeutics offer great potential to transform the biomedical landscape, encompassing the treatment of hereditary conditions and the development of better vaccines. However, the delivery of RNAs into the cell is hampered, among others, by poor endosomal escape. This major hurdle is often tackled using special lipids, polymers, or protein-based delivery vectors. In this review, we will focus on the most prominent peptide- and protein-based endosomal escape strategies with focus on RNA drugs. We discuss cell penetrating peptides, which are still incorporated into novel transfection systems today to promote endosomal escape. However, direct evidence for enhanced endosomal escape by the action of such peptides is missing and their transfection efficiency, even in permissive cell culture conditions, is rather low. Endosomal escape by the help of pore forming proteins or phospholipases, on the other hand, allowed to generate more efficient transfection systems. These are, however, often hampered by considerable toxicity and immunogenicity. We conclude that the perfect enhancer of endosomal escape has yet to be devised. To increase the chances of success, any new transfection system should be tested under relevant conditions and guided by assays that allow direct quantification of endosomal escape.
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Affiliation(s)
- Alexander Klipp
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland.
| | - Michael Burger
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland.
| | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Switzerland.
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16
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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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17
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Steel D, Reid KM, Pisani A, Hess EJ, Fox S, Kurian MA. Advances in targeting neurotransmitter systems in dystonia. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 169:217-258. [PMID: 37482394 DOI: 10.1016/bs.irn.2023.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Dystonia is characterised as uncontrolled, often painful involuntary muscle contractions that cause abnormal postures and repetitive or twisting movements. These movements can be continuous or sporadic and affect different parts of the body and range in severity. Dystonia and its related conditions present a huge cause of neurological morbidity worldwide. Although therapies are available, achieving optimal symptom control without major unwanted effects remains a challenge. Most pharmacological treatments for dystonia aim to modulate the effects of one or more neurotransmitters in the central nervous system, but doing so effectively and with precision is far from straightforward. In this chapter we discuss the physiology of key neurotransmitters, including dopamine, noradrenaline, serotonin (5-hydroxytryptamine), acetylcholine, GABA, glutamate, adenosine and cannabinoids, and their role in dystonia. We explore the ways in which existing pharmaceuticals as well as novel agents, currently in clinical trial or preclinical development, target dystonia, and their respective advantages and disadvantages. Finally, we discuss current and emerging genetic therapies which may be used to treat genetic forms of dystonia.
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Affiliation(s)
- Dora Steel
- UCL GOS Institute of Child Health (Zayed Centre for Research into Rare Diseases in Children), London, United Kingdom; Great Ormond Street Hospital for Children, London, United Kingdom
| | - Kimberley M Reid
- UCL GOS Institute of Child Health (Zayed Centre for Research into Rare Diseases in Children), London, United Kingdom
| | - Antonio Pisani
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; IRCCS Mondino Foundation, Pavia, Italy
| | - Ellen J Hess
- Emory University School of Medicine, CA, United States
| | - Susan Fox
- Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, ON, Canada
| | - Manju A Kurian
- UCL GOS Institute of Child Health (Zayed Centre for Research into Rare Diseases in Children), London, United Kingdom; Great Ormond Street Hospital for Children, London, United Kingdom.
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18
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Khorkova O, Stahl J, Joji A, Volmar CH, Zeier Z, Wahlestedt C. Long non-coding RNA-targeting therapeutics: discovery and development update. Expert Opin Drug Discov 2023; 18:1011-1029. [PMID: 37466388 DOI: 10.1080/17460441.2023.2236552] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 07/20/2023]
Abstract
INTRODUCTION lncRNAs are major players in regulatory networks orchestrating multiple cellular functions, such as 3D chromosomal interactions, epigenetic modifications, gene expression and others. Due to progress in the development of nucleic acid-based therapeutics, lncRNAs potentially represent easily accessible therapeutic targets. AREAS COVERED Currently, significant efforts are directed at studies that can tap the enormous therapeutic potential of lncRNAs. This review describes recent developments in this field, particularly focusing on clinical applications. EXPERT OPINION Extensive druggable target range of lncRNA combined with high specificity and accelerated development process of nucleic acid-based therapeutics open new prospects for treatment in areas of extreme unmet medical need, such as genetic diseases, aggressive cancers, protein deficiencies, and subsets of common diseases caused by known mutations. Although currently wide acceptance of lncRNA-targeting nucleic acid-based therapeutics is impeded by the need for parenteral or direct-to-CNS administration, development of less invasive techniques and orally available/BBB-penetrant nucleic acid-based therapeutics is showing early successes. Recently, mRNA-based COVID-19 vaccines have demonstrated clinical safety of all aspects of nucleic acid-based therapeutic technology, including multiple chemical modifications of nucleic acids and nanoparticle delivery. These trends position lncRNA-targeting drugs as significant players in the future of drug development, especially in the area of personalized medicine.
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Affiliation(s)
- Olga Khorkova
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
| | - Jack Stahl
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
| | - Aswathy Joji
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
| | - Claude-Henry Volmar
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
| | - Zane Zeier
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
| | - Claes Wahlestedt
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
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19
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Khorkova O, Stahl J, Joji A, Volmar CH, Wahlestedt C. Amplifying gene expression with RNA-targeted therapeutics. Nat Rev Drug Discov 2023; 22:539-561. [PMID: 37253858 PMCID: PMC10227815 DOI: 10.1038/s41573-023-00704-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2023] [Indexed: 06/01/2023]
Abstract
Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.
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Affiliation(s)
- Olga Khorkova
- OPKO Health, Miami, FL, USA
- Center for Therapeutic Innovation, University of Miami, Miami, FL, USA
| | - Jack Stahl
- Center for Therapeutic Innovation, University of Miami, Miami, FL, USA
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
| | - Aswathy Joji
- Center for Therapeutic Innovation, University of Miami, Miami, FL, USA
- Department of Chemistry, University of Miami, Miami, FL, USA
| | - Claude-Henry Volmar
- Center for Therapeutic Innovation, University of Miami, Miami, FL, USA
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA
| | - Claes Wahlestedt
- Center for Therapeutic Innovation, University of Miami, Miami, FL, USA.
- Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.
- Department of Chemistry, University of Miami, Miami, FL, USA.
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20
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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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Jiang T, Gonzalez KM, Cordova LE, Lu J. Nanotechnology-enabled gene delivery for cancer and other genetic diseases. Expert Opin Drug Deliv 2023; 20:523-540. [PMID: 37017558 PMCID: PMC10164135 DOI: 10.1080/17425247.2023.2200246] [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: 08/22/2022] [Accepted: 04/04/2023] [Indexed: 04/06/2023]
Abstract
INTRODUCTION Despite gene therapy is ideal for genetic abnormality-related diseases, the easy degradation, poor targeting, and inefficiency in entering targeted cells are plaguing the effective delivery of gene therapy. Viral and non-viral vectors have been used for delivering gene therapeutics in vivo by safeguarding nucleic acid agents to target cells and to reach the specific intracellular location. A variety of nanotechnology-enabled safe and efficient systems have been successfully developed to improve the targeting ability for effective therapeutic delivery of genetic drugs. AREAS COVERED In this review, we outline the multiple biological barriers associated with gene delivery process, and highlight recent advances to gene therapy strategy in vivo, including gene correction, gene silencing, gene activation and genome editing. We point out current developments and challenges exist of non-viral and viral vector systems in association with chemical and physical gene delivery technologies and their potential for the future. EXPERT OPINION This review focuses on the opportunities and challenges to various gene therapy strategy, with specific emphasis on overcoming the challenges through the development of biocompatibility and smart gene vectors for potential clinical application.
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Affiliation(s)
- Tong Jiang
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
| | - Karina Marie Gonzalez
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
| | - Leyla Estrella Cordova
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
| | - Jianqin Lu
- Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, Arizona, 85721, United States
- NCI-designated University of Arizona Comprehensive Cancer Center, Tucson, Arizona, 85721, United States
- BIO5 Institute, The University of Arizona, Tucson, Arizona, 85721, United States
- Southwest Environmental Health Sciences Center, The University of Arizona, Tucson, 85721, United States
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22
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Pushparaj PN, Kalamegam G, Ramakrishna S. Editorial: Methods and application in integrative and regenerative pharmacology: 2021. Front Pharmacol 2022; 13:1077352. [PMID: 36506581 PMCID: PMC9732651 DOI: 10.3389/fphar.2022.1077352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 11/09/2022] [Indexed: 11/27/2022] Open
Affiliation(s)
- Peter Natesan Pushparaj
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia,Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia,Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, India,*Correspondence: Gauthaman Kalamegam, ; Peter Natesan Pushparaj,
| | - Gauthaman Kalamegam
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, India,Pharmaceutical Division, Nibblen Life Sciences, Chennai, India,*Correspondence: Gauthaman Kalamegam, ; Peter Natesan Pushparaj,
| | - Seeram Ramakrishna
- Center for Nanofibers & Nanotechnology, Department of Mechanical Engineering, National University of Singapore, Singapore, Singapore
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23
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Noncoding RNAs Emerging as Drugs or Drug Targets: Their Chemical Modification, Bio-Conjugation and Intracellular Regulation. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27196717. [PMID: 36235253 PMCID: PMC9573214 DOI: 10.3390/molecules27196717] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/06/2022] [Accepted: 10/07/2022] [Indexed: 11/07/2022]
Abstract
With the increasing understanding of various disease-related noncoding RNAs, ncRNAs are emerging as novel drugs and drug targets. Nucleic acid drugs based on different types of noncoding RNAs have been designed and tested. Chemical modification has been applied to noncoding RNAs such as siRNA or miRNA to increase the resistance to degradation with minimum influence on their biological function. Chemical biological methods have also been developed to regulate relevant noncoding RNAs in the occurrence of various diseases. New strategies such as designing ribonuclease targeting chimeras to degrade endogenous noncoding RNAs are emerging as promising approaches to regulate gene expressions, serving as next-generation drugs. This review summarized the current state of noncoding RNA-based theranostics, major chemical modifications of noncoding RNAs to develop nucleic acid drugs, conjugation of RNA with different functional biomolecules as well as design and screening of potential molecules to regulate the expression or activity of endogenous noncoding RNAs for drug development. Finally, strategies of improving the delivery of noncoding RNAs are discussed.
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Khorkova O, Stahl J, Joji A, Volmar CH, Zeier Z, Wahlestedt C. Natural antisense transcripts as drug targets. Front Mol Biosci 2022; 9:978375. [PMID: 36250017 PMCID: PMC9563854 DOI: 10.3389/fmolb.2022.978375] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/30/2022] [Indexed: 11/13/2022] Open
Abstract
The recent discovery of vast non-coding RNA-based regulatory networks that can be easily modulated by nucleic acid-based drugs has opened numerous new therapeutic possibilities. Long non-coding RNA, and natural antisense transcripts (NATs) in particular, play a significant role in networks that involve a wide variety of disease-relevant biological mechanisms such as transcription, splicing, translation, mRNA degradation and others. Currently, significant efforts are dedicated to harnessing these newly emerging NAT-mediated biological mechanisms for therapeutic purposes. This review will highlight the recent clinical and pre-clinical developments in this field and survey the advances in nucleic acid-based drug technologies that make these developments possible.
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Affiliation(s)
- Olga Khorkova
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States
| | - Jack Stahl
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States
| | - Aswathy Joji
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States
- Department of Chemistry, University of Miami, Miami, FL, United States
| | - Claude-Henry Volmar
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States
| | - Zane Zeier
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States
| | - Claes Wahlestedt
- Center for Therapeutic Innovation and Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, United States
- Department of Chemistry, University of Miami, Miami, FL, United States
- *Correspondence: Claes Wahlestedt,
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Zhang Z, Wang L, Wang Z, Zhang T, Shi M, Xin C, Zou Y, Wei W, Li X, Chen J, Zhao W. Lysosomal-associated transmembrane protein 5 deficiency exacerbates cerebral ischemia/reperfusion injury. Front Mol Neurosci 2022; 15:971361. [PMID: 36046710 PMCID: PMC9423384 DOI: 10.3389/fnmol.2022.971361] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Lysosomal-associated transmembrane protein 5 (LAPTM5) has been demonstrated to be involved in regulating immunity, inflammation, cell death, and autophagy in the pathophysiological processes of many diseases. However, the function of LAPTM5 in cerebral ischemia-reperfusion (I/R) injury has not yet been reported. In this study, we found that LAPTM5 expression was dramatically decreased during cerebral I/R injury both in vivo and in vitro. LAPTM5 knockout (KO) mice were compared with a control, and they showed a larger infarct size and more serious neurological dysfunction after transient middle cerebral artery occlusion (tMCAO) treatment. In addition, inflammatory response and apoptosis were exacerbated in these processes. Furthermore, gain- and loss-of-function investigations in an in vitro model revealed that neuronal inflammation and apoptosis were aggravated by LAPTM5 knockdown but mitigated by its overexpression. Mechanistically, combined RNA sequencing and experimental verification showed that the apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase (JNK)/p38 pathway was mainly involved in the detrimental effects of LAPTM5 deficiency following I/R injury. Specifically, LAPTM5 directly interacts with ASK1, leading to decreased ASK1 N-terminal dimerization and the subsequent reduced activation of downstream JNK/p38 signaling. In conclusion, LAPTM5 was demonstrated to be a novel modulator in the pathophysiology of brain I/R injury, and targeting LAPTM5 may be feasible as a stroke treatment.
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Affiliation(s)
- Zongyong Zhang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Lei Wang
- Department of Neurosurgery, Huanggang Central Hospital, Huanggang, China
| | - Zhen Wang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Tingbao Zhang
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Min Shi
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Can Xin
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yichun Zou
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Wei Wei
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Xiang Li
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Jincao Chen
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- *Correspondence: Jincao Chen,
| | - Wenyuan Zhao
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
- Wenyuan Zhao,
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Zhu Y, Zhu L, Wang X, Jin H. RNA-based therapeutics: an overview and prospectus. Cell Death Dis 2022; 13:644. [PMID: 35871216 PMCID: PMC9308039 DOI: 10.1038/s41419-022-05075-2] [Citation(s) in RCA: 285] [Impact Index Per Article: 95.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 01/21/2023]
Abstract
The growing understanding of RNA functions and their crucial roles in diseases promotes the application of various RNAs to selectively function on hitherto "undruggable" proteins, transcripts and genes, thus potentially broadening the therapeutic targets. Several RNA-based medications have been approved for clinical use, while others are still under investigation or preclinical trials. Various techniques have been explored to promote RNA intracellular trafficking and metabolic stability, despite significant challenges in developing RNA-based therapeutics. In this review, the mechanisms of action, challenges, solutions, and clinical application of RNA-based therapeutics have been comprehensively summarized.
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Affiliation(s)
- Yiran Zhu
- grid.13402.340000 0004 1759 700XLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang China
| | - Liyuan Zhu
- grid.13402.340000 0004 1759 700XLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang China
| | - Xian Wang
- grid.13402.340000 0004 1759 700XDepartment of Medical Oncology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang China
| | - Hongchuan Jin
- grid.13402.340000 0004 1759 700XLaboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang China
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