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Liu Y, Lu K, Zhang R, Hu D, Yang Z, Zeng J, Cai W. Advancements in the Treatment of Atherosclerosis: From Conventional Therapies to Cutting-Edge Innovations. ACS Pharmacol Transl Sci 2024; 7:3804-3826. [PMID: 39698263 PMCID: PMC11651175 DOI: 10.1021/acsptsci.4c00574] [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: 09/26/2024] [Revised: 11/18/2024] [Accepted: 11/20/2024] [Indexed: 12/20/2024]
Abstract
Atherosclerosis is a leading cause of morbidity and mortality worldwide, driven by a complex interplay of lipid dysregulation, inflammation, and vascular pathology. Despite advancements in understanding the multifactorial nature of atherosclerosis and improvements in clinical management, existing therapies often fall short in reversing the disease, focusing instead on symptom alleviation and risk reduction. This review highlights recent strides in identifying genetic markers, elucidating inflammatory pathways, and understanding environmental contributors to atherosclerosis. It also evaluates the efficacy and limitations of current pharmacological treatments, revascularization techniques, and the impact of these interventions on patient outcomes. Furthermore, we explore innovative therapeutic strategies, including the promising fields of nanomedicine, nucleic acid-based therapies, and immunomodulation, which offer potential for targeted and effective treatment modalities. However, integrating these advances into clinical practice is challenged by regulatory, economic, and logistical barriers. This review synthesizes the latest research and clinical advancements to provide a comprehensive roadmap for future therapeutic strategies and emphasize the critical need for innovative approaches to fundamentally change the course of atherosclerosis management.
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Affiliation(s)
- Yan Liu
- The
Second Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Center
for Molecular Imaging and Nuclear Medicine, State Key Laboratory of
Radiation Medicine and Protection, School for Radiological and Interdisciplinary
Sciences (RAD-X), Collaborative Innovation Center of Radiological
Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Kuan Lu
- The
Second Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Ruru Zhang
- Center
for Molecular Imaging and Nuclear Medicine, State Key Laboratory of
Radiation Medicine and Protection, School for Radiological and Interdisciplinary
Sciences (RAD-X), Collaborative Innovation Center of Radiological
Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Dongliang Hu
- The
Second Affiliated Hospital of Soochow University, Suzhou, 215000, China
- Center
for Molecular Imaging and Nuclear Medicine, State Key Laboratory of
Radiation Medicine and Protection, School for Radiological and Interdisciplinary
Sciences (RAD-X), Collaborative Innovation Center of Radiological
Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Zhe Yang
- The
Second Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Jianfeng Zeng
- Center
for Molecular Imaging and Nuclear Medicine, State Key Laboratory of
Radiation Medicine and Protection, School for Radiological and Interdisciplinary
Sciences (RAD-X), Collaborative Innovation Center of Radiological
Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China
| | - Wu Cai
- The
Second Affiliated Hospital of Soochow University, Suzhou, 215000, China
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Gil-Cabrerizo P, Simon-Yarza T, Garbayo E, Blanco-Prieto MJ. Navigating the landscape of RNA delivery systems in cardiovascular disease therapeutics. Adv Drug Deliv Rev 2024; 208:115302. [PMID: 38574952 DOI: 10.1016/j.addr.2024.115302] [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: 11/28/2023] [Revised: 03/21/2024] [Accepted: 03/28/2024] [Indexed: 04/06/2024]
Abstract
Cardiovascular diseases (CVDs) stand as the leading cause of death worldwide, posing a significant global health challenge. Consequently, the development of innovative therapeutic strategies to enhance CVDs treatment is imperative. RNA-based therapies, encompassing non-coding RNAs, mRNA, aptamers, and CRISPR/Cas9 technology, have emerged as promising tools for addressing CVDs. However, inherent challenges associated with RNA, such as poor cellular uptake, susceptibility to RNase degradation, and capture by the reticuloendothelial system, underscore the necessity of combining these therapies with effective drug delivery systems. Various non-viral delivery systems, including extracellular vesicles, lipid-based carriers, polymeric and inorganic nanoparticles, as well as hydrogels, have shown promise in enhancing the efficacy of RNA therapeutics. In this review, we offer an overview of the most relevant RNA-based therapeutic strategies explored for addressing CVDs and emphasize the pivotal role of delivery systems in augmenting their effectiveness. Additionally, we discuss the current status of these therapies and the challenges that hinder their clinical translation.
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Affiliation(s)
- Paula Gil-Cabrerizo
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Nutrition, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Navarra Institute for Health Research, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain
| | - Teresa Simon-Yarza
- Université Paris Cité, Université Sorbonne Paris Nord, Laboratory for Vascular Translational Science, INSERM U1148, X. Bichat Hospital, Paris 75018, France
| | - Elisa Garbayo
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Nutrition, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Navarra Institute for Health Research, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain.
| | - María J Blanco-Prieto
- Department of Pharmaceutical Sciences, Faculty of Pharmacy and Nutrition, University of Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Navarra Institute for Health Research, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain.
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3
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Qureshi Z, Khanzada M, Safi A, Fatima E, Altaf F, Vittorio TJ. Hypercholesterolemia: a literature review on management using tafolecimab: a novel member of PCSK9 monoclonal antibodies. Ann Med Surg (Lond) 2024; 86:2818-2827. [PMID: 38694324 PMCID: PMC11060207 DOI: 10.1097/ms9.0000000000001945] [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: 12/05/2023] [Accepted: 03/02/2024] [Indexed: 05/04/2024] Open
Abstract
Background Cardiovascular diseases (CVD) persist as the leading cause of mortality globally, with atherosclerotic cardiovascular disease (ASCVD), including hypercholesterolaemia, being a significant contributor. Hyperlipidemia management includes various lipid-lowering drugs, including statins, Bempedoic acid, inclisiran, Lomitapide, ANGPTL3 inhibitors, and PCSK9 inhibitors. Statins have traditionally dominated lipid management therapies; however, a subset of patients remains unresponsive or intolerant to this therapy, necessitating novel therapeutic approaches. Tafolecimab, a promising and novel PCSK9 monoclonal antibody, demonstrated significant LDL-C reduction and a favourable safety profile in clinical trials. Objective This review aimed to discuss the role and efficacy of Tafolecimab in the management of hypercholesterolaemia. Methods The authors searched online databases, including PubMed, Scopus, and Embase, for articles related to talofecimab. Discussion The efficacy of Tafolecimab in diverse patient populations, including those with comorbid conditions and various lipid disorders, has been explored. Ongoing trials, such as CREDIT-1, CREDIT-2, and CREDIT-4, have provided valuable insights into Tafolecimab's potential as a lipid-lowering agent. Moreover, the drug's extended dosing interval may enhance patient compliance and reduce treatment costs. It has also been found that Tafolecimab has more affinity for PCSK9 and a longer duration of LDL-C reduction than other monoclonal antibody drugs such as evolocumab. Thus, this review focuses on Tafolecimab, a novel PCSK9 monoclonal antibody, its mechanism of action, clinical trial outcomes, safety profile, and potential role in hypercholesterolaemia management. Despite its assuring potential, the long-term impact of Tafolecimab on cardiovascular outcomes remains to be fully elucidated, necessitating further research. Regulatory authorities like the FDA and EMA should also evaluate Tafolecimab's risks and benefits. Conclusion In conclusion, Tafolecimab shows potential as an innovative therapeutic option for hypercholesterolaemia, particularly in patients with specific risk factors, but warrants additional research.
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Affiliation(s)
- Zaheer Qureshi
- The Frank H. Netter M.D. School of Medicine at Quinnipiac University, Bridgeport, CT
| | - Mikail Khanzada
- Department of Internal Medicine, Lahore Medical & Dental College
| | - Adnan Safi
- Department of Medicine, Lahore General Hospital
| | - Eeshal Fatima
- Department of Medicine, Services Institute of Medical Sciences, Lahore, Pakistan
| | - Faryal Altaf
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/BronxCare Health System
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Gill PK, Hegele RA. New Biological Therapies for Low-Density Lipoprotein Cholesterol. Can J Cardiol 2023; 39:1913-1930. [PMID: 37562541 DOI: 10.1016/j.cjca.2023.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/12/2023] Open
Abstract
Depressed low-density lipoprotein cholesterol concentration protects against atherosclerotic cardiovascular disease. Natural hypocholesterolemia states can have a monogenic etiology, caused by pathogenic loss of function variants in the PCSK9, ANGPTL3, MTTP, or APOB genes. In this focused review, we discuss development and clinical use of several new therapeutics that inhibit these gene products to target elevated levels of low-density lipoprotein cholesterol. In particular, inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) have notably affected clinical practice, followed recently by inhibition of angiopoietin-like 3 (ANGPTL3). Currently used in the clinic are alirocumab and evolocumab, two anti-PCSK9 monoclonal antibodies, inclisiran, a small interfering RNA that prevents PCSK9 translation, evinacumab, an anti-ANGPTL3 monoclonal antibody, and lomitapide, a small-molecule inhibitor of microsomal triglyceride transfer protein. Additional therapies are in preclinical or clinical trial stages of development. These consist of other monoclonal antibodies, antisense oligonucleotides, small-molecule inhibitors, mimetic peptides, adnectins, vaccines, and gene-editing therapies. Vaccines and gene-editing therapies in particular hold great potential to confer active long-term attenuation or provide single-treatment life-long knock-down of PCSK9 or ANGPTL3 activity. Biologic therapies inspired by monogenic hypocholesterolemia states are becoming valuable tools to help protect against atherosclerotic cardiovascular disease.
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Affiliation(s)
- Praneet K Gill
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Robert A Hegele
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
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5
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Oza PP, Kashfi K. The evolving landscape of PCSK9 inhibition in cancer. Eur J Pharmacol 2023; 949:175721. [PMID: 37059376 PMCID: PMC10229316 DOI: 10.1016/j.ejphar.2023.175721] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/23/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Cancer is a disease with a significant global burden in terms of premature mortality, loss of productivity, healthcare expenditures, and impact on mental health. Recent decades have seen numerous advances in cancer research and treatment options. Recently, a new role of cholesterol-lowering PCSK9 inhibitor therapy has come to light in the context of cancer. PCSK9 is an enzyme that induces the degradation of low-density lipoprotein receptors (LDLRs), which are responsible for clearing cholesterol from the serum. Thus, PCSK9 inhibition is currently used to treat hypercholesterolemia, as it can upregulate LDLRs and enable cholesterol reduction through these receptors. The cholesterol-lowering effects of PCSK9 inhibitors have been suggested as a potential mechanism to combat cancer, as cancer cells have been found to increasingly rely on cholesterol for their growth needs. Additionally, PCSK9 inhibition has demonstrated the potential to induce cancer cell apoptosis through several pathways, increase the efficacy of a class of existing anticancer therapies, and boost the host immune response to cancer. A role in managing cancer- or cancer treatment-related development of dyslipidemia and life-threatening sepsis has also been suggested. This review examines the current evidence regarding the effects of PCSK9 inhibition in the context of different cancers and cancer-associated complications.
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Affiliation(s)
- Palak P Oza
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, 10091, USA.
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6
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Valenzuela A, Ayuso M, Buyssens L, Bars C, Van Ginneken C, Tessier Y, Van Cruchten S. Platelet Activation by Antisense Oligonucleotides (ASOs) in the Göttingen Minipig, including an Evaluation of Glycoprotein VI (GPVI) and Platelet Factor 4 (PF4) Ontogeny. Pharmaceutics 2023; 15:pharmaceutics15041112. [PMID: 37111598 PMCID: PMC10143489 DOI: 10.3390/pharmaceutics15041112] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/06/2023] [Accepted: 03/30/2023] [Indexed: 04/03/2023] Open
Abstract
Antisense oligonucleotide (ASO) is a therapeutic modality that enables selective modulation of undruggable protein targets. However, dose- and sequence-dependent platelet count reductions have been reported in nonclinical studies and clinical trials. The adult Göttingen minipig is an acknowledged nonclinical model for ASO safety testing, and the juvenile Göttingen minipig has been recently proposed for the safety testing of pediatric medicines. This study assessed the effects of various ASO sequences and modifications on Göttingen minipig platelets using in vitro platelet activation and aggregometry assays. The underlying mechanism was investigated further to characterize this animal model for ASO safety testing. In addition, the protein abundance of glycoprotein VI (GPVI) and platelet factor 4 (PF4) was investigated in the adult and juvenile minipigs. Our data on direct platelet activation and aggregation by ASOs in adult minipigs are remarkably comparable to human data. Additionally, PS ASOs bind to platelet collagen receptor GPVI and directly activate minipig platelets in vitro, mirroring the findings in human blood samples. This further corroborates the use of the Göttingen minipig for ASO safety testing. Moreover, the differential abundance of GPVI and PF4 in minipigs provides insight into the influence of ontogeny in potential ASO-induced thrombocytopenia in pediatric patients.
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Goyenvalle A, Jimenez-Mallebrera C, van Roon W, Sewing S, Krieg AM, Arechavala-Gomeza V, Andersson P. Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides. Nucleic Acid Ther 2023; 33:1-16. [PMID: 36579950 PMCID: PMC9940817 DOI: 10.1089/nat.2022.0061] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network "DARTER," a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity in vitro or ex vivo to filter out potential toxic candidates before moving to in vivo phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human in vitro systems. Yet, small preliminary in vivo studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.
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Affiliation(s)
- Aurélie Goyenvalle
- Université Paris-Saclay, UVSQ, Inserm, END-ICAP, Versailles, France.,Address correspondence to: Aurélie Goyenvalle, PhD, Université Paris-Saclay, UVSQ, Inserm, END-ICAP, Versailles 78000, France
| | - Cecilia Jimenez-Mallebrera
- Laboratorio de Investigación Aplicada en Enfermedades Neuromusculares, Unidad de Patología Neuromuscular, Servicio de Neuropediatría, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain.,Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Departamento de Genética, Microbiología y Estadística, Universitat de Barcelona, Barcelona, Spain
| | - Willeke van Roon
- Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Sabine Sewing
- Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland
| | - Arthur M. Krieg
- RNA Therapeutics Institute, University of Massachusetts, Worcester, Massachusetts, USA
| | - Virginia Arechavala-Gomeza
- Neuromuscular Disorders, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain.,Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Patrik Andersson
- Safety Innovation, Safety Sciences, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden.,Address correspondence to: Patrik Andersson, PhD, Safety Innovation, Safety Sciences, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Pepparedsleden 1, Mölndal, Gothenburg 431 83, Sweden
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Kovács ÁF. Gene Therapy of Extracellular Vesicles in Cardiovascular and Metabolic Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1418:207-228. [PMID: 37603282 DOI: 10.1007/978-981-99-1443-2_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
The ultimate and most complex form of treating human diseases is embodied by gene therapy. For an effective gene therapeutic product we need to hack the cellular plasma membrane entry-system, then escaping degradation in the cytosol and in most cases, we need an efficient hacking of the nuclear membrane-system, achieving the delivery of genetic construct into the central stage of the target cells: nucleoplasm or chromosomal DNA found in this highly controlled space. These steps need to be performed in a targeted, ordered, and efficient way. Possessing intrinsic ability of nucleic acid and protein delivery, extracellular vesicles can bypass biological barriers and may be able to deliver a next-generation platform for gene therapy. Fine-tuned genetic constructs included in (synthetic) extracellular vesicles may provide an upgraded approach to the current gene therapeutical technologies by significantly upgrading and improving biosafety, versatility, and delivery, thus evoking the desired therapeutic response. This chapter addresses the main types, vectors, challenges, and safety issues of gene therapy. Afterwards, a brief introduction and beneficial roles of extracellular vesicles are given. The concept of engineering vesicles for gene therapy is also discussed. A snapshot of most relevant clinical trials in the field of cardiovascular and metabolic diseases is shown. Finally, a wrap-up and outlook about gene therapy are presented.
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Affiliation(s)
- Árpád Ferenc Kovács
- Department of Paediatrics, Semmelweis University, Budapest, Hungary.
- For Human Genome Foundation, Budapest, Hungary.
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Alannan M, Seidah NG, Merched AJ. PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity. Cells 2022; 11:cells11244132. [PMID: 36552895 PMCID: PMC9777286 DOI: 10.3390/cells11244132] [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: 10/13/2022] [Revised: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver.
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Affiliation(s)
- Malak Alannan
- Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France
| | - Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, IRCM, University of Montreal, Montreal, QC H2W 1R7, Canada
| | - Aksam J. Merched
- Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France
- Correspondence:
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Ahamad S, Bhat SA. Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment. J Med Chem 2022; 65:15513-15539. [PMID: 36446632 DOI: 10.1021/acs.jmedchem.2c01290] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
The proprotein convertase subtilisin/kexin-type 9 (PCSK9) binds to low-density lipoprotein receptors (LDLR), thereby trafficking them to lysosomes upon endocytosis and enhancing intracellular degradation to prevent their recycling. As a result, the levels of circulating LDL cholesterol (LDL-C) increase, which is a prominent risk factor for developing atherosclerotic cardiovascular diseases (ASCVD). Thus, PCSK9 has become a promising therapeutic target that offers a fertile testing ground for new drug modalities to regulate plasma LDL-C levels to prevent ASCVD. In this review, we have discussed the role of PCSK9 in lipid metabolism and briefly summarized the current clinical status of modalities targeting PCSK9. In particular, a detailed overview of peptide-based PCSK9 inhibitors is presented, which emphasizes their structural features and design, therapeutic effects on patients, and preclinical cardiovascular disease (CVD) models, along with PCSK9 modulation mechanisms. As a promising alternative to monoclonal antibodies (mAbs) for managing LDL-C, anti-PCSK9 peptides are emerging as a prospective next generation therapy.
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Affiliation(s)
- Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India
| | - Shahnawaz A Bhat
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
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11
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Keshavarz Alikhani H, Pourhamzeh M, Seydi H, Shokoohian B, Hossein-khannazer N, Jamshidi-adegani F, Al-Hashmi S, Hassan M, Vosough M. Regulatory Non-Coding RNAs in Familial Hypercholesterolemia, Theranostic Applications. Front Cell Dev Biol 2022; 10:894800. [PMID: 35813199 PMCID: PMC9260315 DOI: 10.3389/fcell.2022.894800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
Familial hypercholesterolemia (FH) is a common monogenic disease which is associated with high serum levels of low-density lipoprotein cholesterol (LDL-C) and leads to atherosclerosis and cardiovascular disease (CVD). Early diagnosis and effective treatment strategy can significantly improve prognosis. Recently, non-coding RNAs (ncRNAs) have emerged as novel biomarkers for the diagnosis and innovative targets for therapeutics. Non-coding RNAs have essential roles in the regulation of LDL-C homeostasis, suggesting that manipulation and regulating ncRNAs could be a promising theranostic approach to ameliorate clinical complications of FH, particularly cardiovascular disease. In this review, we briefly discussed the mechanisms and pathophysiology of FH and novel therapeutic strategies for the treatment of FH. Moreover, the theranostic effects of different non-coding RNAs for the treatment and diagnosis of FH were highlighted. Finally, the advantages and disadvantages of ncRNA-based therapies vs. conventional therapies were discussed.
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Affiliation(s)
- Hani Keshavarz Alikhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Pourhamzeh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Homeyra Seydi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Bahare Shokoohian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nikoo Hossein-khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Jamshidi-adegani
- Laboratory for Stem Cell and Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Sulaiman Al-Hashmi
- Laboratory for Stem Cell and Regenerative Medicine, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
- *Correspondence: Massoud Vosough,
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12
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Chen R, Lin S, Chen X. The promising novel therapies for familial hypercholesterolemia. J Clin Lab Anal 2022; 36:e24552. [PMID: 35712827 PMCID: PMC9279988 DOI: 10.1002/jcla.24552] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Background The incidence of premature atherosclerotic cardiovascular disease in familial hypercholesterolemia (FH) is high. In recent years, novel therapeutic modalities have shown significant lipid‐lowering ability. In this paper, we summarize the recent developments in novel therapies for FH via the treatment of different targets and discuss the characteristics of each targeted therapy. Based on the process of protein synthesis, we attempt to summarize the direct‐effect targets including protein, RNA, and DNA. Methods For this systematic review, relevant studies are assessed by searching in several databases including PubMed, Web of Science, Scopus, and Google Scholar. The publications of original researches are considered for screening. Results Most drugs are protein‐targeted such as molecule‐based and monoclonal antibodies, including statins, ezetimibe, alirocumab, evolocumab, and evinacumab. Both antisense oligonucleotide (ASO) and small interfering RNA (siRNA) approaches, such as mipomersen, vupanorsen, inclisiran, and ARO‐ANG3, are designed to reduce the number of mRNA transcripts and then degrade proteins. DNA‐targeted therapies such as adeno‐associated virus or CRISPR–Cas9 modification could be used to deliver or edit genes to address a genetic deficiency and improve the related phenotype. Conclusion While the therapies based on different targets including protein, RNA, and DNA are on different stages of development, the mechanisms of these novel therapies may provide new ideas for precision medicine.
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Affiliation(s)
- Ruoyu Chen
- School of Medicine of Ningbo University, Ningbo, China
| | - Shaoyi Lin
- The Affiliated Ningbo First Hospital, School of Medicine of Ningbo University, Ningbo, China
| | - Xiaomin Chen
- The Affiliated Ningbo First Hospital, School of Medicine of Ningbo University, Ningbo, China.,Ningbo First Hospital Affiliated to School of Medicine of Zhejiang University, Ningbo, China
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13
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Marouf BH, Iqbal Z, Mohamad JB, Bashir B, Schofield J, Syed A, Kilpatrick ES, Stefanutti C, Soran H. Efficacy and Safety of PCSK9 Monoclonal Antibodies in Patients With Diabetes. Clin Ther 2022; 44:331-348. [PMID: 35246337 DOI: 10.1016/j.clinthera.2021.12.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/28/2021] [Accepted: 12/09/2021] [Indexed: 11/28/2022]
Abstract
PURPOSE Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have proven efficacy in improving cardiovascular outcomes. Roles for the PCSK9 molecule in metabolic pathways beyond LDL receptor processing and cholesterol homeostasis are well established. PCSK9 genetic variants associated with lower LDL-C levels correlate with a higher incidence of type 2 diabetes (T2DM), calling into question the appropriateness of these drugs in patients with T2DM and those at high risk of developing diabetes, and whether cardiovascular benefit seen with PCSK9 inhibitors might be offset by resultant dysglycemia. The purpose of this review was to examine the role of PCSK9 protein in glucose homeostasis, the impact of PCSK9 inhibition in relation to glucose homeostasis, and whether some of the cardiovascular benefit seen with PCSK9 inhibitors and statins might be offset by resultant dysglycemia. METHODS Comprehensive literature searches of electronic databases of PubMed, EMBASE, and OVID were conducted by using the search terms hyperlipidaemia, PCSK9, diabetes, and glucose as well as other relevant papers of interest collected by the authors. The retrieved papers were reviewed and shortlisted most relevant ones. FINDINGS Genetically determined lower circulating LDL-C and PCSK9 concentrations may have an incremental effect in increasing T2DM incidence, but any perceived harm is outweighed by the reduced risk of atherosclerotic cardiovascular disease achieved through lower lifetime exposure to LDL-C. PCSK9 monoclonal antibodies are effective and safe in patients with T2DM and those at high risk of developing it. The number-needed-to-treat to prevent one atherosclerotic cardiovascular disease event in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study in the subgroup with diabetes is significantly lower than for those without. Therefore, T2DM or being at high risk to develop it should not be a reason to avoid these agents. The safety of PCSK9 inhibition in relation to glucose homeostasis may depend on the method of inhibition and whether it occurs in circulation or the cells. Data from experimental studies and randomized controlled trials suggest no detrimental effect of PCSK9 monoclonal antibodies on glucose homeostasis. More data and large randomized controlled studies are needed to assess the impact of other methods of PCSK9 inhibition on glucose homeostasis. IMPLICATIONS PCSK9monoclonal antibodies markedly reduce LDL-C and consistently reduce cardiovascular mortality in patients with and without diabetes. Current evidence does not suggest an adverse effect of PCSK9 monoclonal antibodies on glycemic parameters.
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Affiliation(s)
- Bushra Hassan Marouf
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani, Federal Region of Kurdistan, Iraq
| | - Zohaib Iqbal
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Jamal Basheer Mohamad
- Department of Internal Medicine, College of Medicine, University of Duhok, Duhok, Federal Region of Kurdistan, Iraq
| | - Bilal Bashir
- Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Jonathan Schofield
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Akheel Syed
- Department of Diabetes, Endocrinology and Obesity Medicine, Salford Royal NHS Foundation and University Teaching Trust, Salford, United Kingdom
| | - Eric S Kilpatrick
- Department of Clinical Biochemistry, Manchester University NHS Foundation Trust, Manchester, and Hull York Medical School, Hull, United Kingdom
| | - Claudia Stefanutti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Handrean Soran
- Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
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14
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Delivery of Oligonucleotides: Efficiency with Lipid Conjugation and Clinical Outcome. Pharmaceutics 2022; 14:pharmaceutics14020342. [PMID: 35214074 PMCID: PMC8879684 DOI: 10.3390/pharmaceutics14020342] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 11/21/2022] Open
Abstract
Oligonucleotides have shifted drug discovery into a new paradigm due to their ability to silence the genes and inhibit protein translation. Importantly, they can drug the un-druggable targets from the conventional small-molecule perspective. Unfortunately, poor cellular permeability and susceptibility to nuclease degradation remain as major hurdles for the development of oligonucleotide therapeutic agents. Studies of safe and effective delivery technique with lipid bioconjugates gains attention to resolve these issues. Our review article summarizes the physicochemical effect of well-studied hydrophobic moieties to enhance the cellular entry of oligonucleotides. The structural impacts of fatty acids, cholesterol, tocopherol, and squalene on cellular internalization and membrane penetration in vitro and in vivo were discussed first. The crucial assays for delivery evaluation within this section were analyzed sequentially. Next, we provided a few successful examples of lipid-conjugated oligonucleotides advanced into clinical studies for treating patients with different medical backgrounds. Finally, we pinpointed current limitations and outlooks in this research field along with opportunities to explore new modifications and efficacy studies.
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15
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Wada F, Yamamoto T, Kobayashi T, Tachibana K, Ito KR, Hamasaki M, Kayaba Y, Terada C, Yamayoshi A, Obika S, Harada-Shiba M. Drug discovery and development scheme for liver-targeting bridged nucleic acid antisense oligonucleotides. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:957-969. [PMID: 34760338 PMCID: PMC8560717 DOI: 10.1016/j.omtn.2021.10.008] [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] [Received: 03/05/2021] [Revised: 08/15/2021] [Accepted: 10/06/2021] [Indexed: 11/21/2022]
Abstract
Antisense oligonucleotides (ASOs) containing bridged nucleic acids (BNAs) have been proven to be very powerful. However, ensuring a reliable discovery and translational development scheme for this class of ASOs with wider therapeutic windows remains a fundamental challenge. We here demonstrate the robustness of our scheme in the context of the selection of ASOs having two different BNA chemistries (2,′4′-BNA/locked nucleic acid [LNA] and amido-bridged nucleic acid [AmNA]) targeting human proprotein convertase subtilisin/kexin type 9 (PCSK9). The scheme features a two-step process, including (1) a unique and sensitive in vitro screening approach, called Ca2+ enrichment of medium (CEM) transfection, and (2) a ligand-targeted drug delivery approach to better reach target tissues, averting unintended accumulation of ASOs. Using CEM screening, we identified a candidate ASO that shows >70% cholesterol-lowering action in monkeys. An N-acetylgalactosamine (GalNAc) ligand then was appended to the candidate ASO to further broaden the therapeutic margin by altering the molecule’s pharmacokinetics. The GalNAc conjugate, HsPCSK9-1811-LNA, was found to be at least ten times more potent in non-human primates (compared with the unconjugated counterpart), with reduced nephrotoxicity in rats. Overall, we successfully showed that our drug development scheme is better suited for selecting clinically relevant BNA-based ASOs, especially for the treatment of liver-associated diseases.
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Affiliation(s)
- Fumito Wada
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan.,Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan.,Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Tsuyoshi Yamamoto
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.,Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8131, Japan
| | - Tadayuki Kobayashi
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan.,Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan.,Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Keisuke Tachibana
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kosuke Ramon Ito
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Mayumi Hamasaki
- Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan
| | - Yukina Kayaba
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8131, Japan
| | - Chisato Terada
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8131, Japan
| | - Asako Yamayoshi
- Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8131, Japan
| | - Satoshi Obika
- Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Mariko Harada-Shiba
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan.,Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-shinmachi, Suita, Osaka 564-8565, Japan
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16
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Valenzuela A, Tardiveau C, Ayuso M, Buyssens L, Bars C, Van Ginneken C, Fant P, Leconte I, Braendli-Baiocco A, Parrott N, Schmitt G, Tessier Y, Barrow P, Van Cruchten S. Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases. Pharmaceutics 2021; 13:1442. [PMID: 34575518 PMCID: PMC8470776 DOI: 10.3390/pharmaceutics13091442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/06/2021] [Accepted: 09/07/2021] [Indexed: 11/16/2022] Open
Abstract
The adult Göttingen Minipig is an acknowledged model for safety assessment of antisense oligonucleotide (ASO) drugs developed for adult indications. To assess whether the juvenile Göttingen Minipig is also a suitable nonclinical model for pediatric safety assessment of ASOs, we performed an 8-week repeat-dose toxicity study in different age groups of minipigs ranging from 1 to 50 days of age. The animals received a weekly dose of a phosphorothioated locked-nucleic-acid-based ASO that was assessed previously for toxicity in adult minipigs. The endpoints included toxicokinetic parameters, in-life monitoring, clinical pathology, and histopathology. Additionally, the ontogeny of key nucleases involved in ASO metabolism and pharmacologic activity was investigated using quantitative polymerase chain reaction and nuclease activity assays. Similar clinical chemistry and toxicity findings were observed; however, differences in plasma and tissue exposures as well as pharmacologic activity were seen in the juvenile minipigs when compared with the adult data. The ontogeny study revealed a differential nuclease expression and activity, which could affect the metabolic pathway and pharmacologic effect of ASOs in different tissues and age groups. These data indicate that the juvenile Göttingen Minipig is a promising nonclinical model for safety assessment of ASOs intended to treat disease in the human pediatric population.
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Affiliation(s)
- Allan Valenzuela
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (A.V.); (M.A.); (L.B.); (C.B.); (C.V.G.)
| | - Claire Tardiveau
- Charles River Laboratories France Safety Assessment SAS, 69210 Saint-Germain-Nuelles, France; (C.T.); (P.F.); (I.L.)
| | - Miriam Ayuso
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (A.V.); (M.A.); (L.B.); (C.B.); (C.V.G.)
| | - Laura Buyssens
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (A.V.); (M.A.); (L.B.); (C.B.); (C.V.G.)
| | - Chloe Bars
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (A.V.); (M.A.); (L.B.); (C.B.); (C.V.G.)
| | - Chris Van Ginneken
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (A.V.); (M.A.); (L.B.); (C.B.); (C.V.G.)
| | - Pierluigi Fant
- Charles River Laboratories France Safety Assessment SAS, 69210 Saint-Germain-Nuelles, France; (C.T.); (P.F.); (I.L.)
| | - Isabelle Leconte
- Charles River Laboratories France Safety Assessment SAS, 69210 Saint-Germain-Nuelles, France; (C.T.); (P.F.); (I.L.)
| | - Annamaria Braendli-Baiocco
- Roche Pharmaceutical Research and Early Development, F. Hoffmann-La-Roche, Ltd., 4070 Basel, Switzerland; (A.B.-B.); (N.P.); (G.S.); (Y.T.); (P.B.)
| | - Neil Parrott
- Roche Pharmaceutical Research and Early Development, F. Hoffmann-La-Roche, Ltd., 4070 Basel, Switzerland; (A.B.-B.); (N.P.); (G.S.); (Y.T.); (P.B.)
| | - Georg Schmitt
- Roche Pharmaceutical Research and Early Development, F. Hoffmann-La-Roche, Ltd., 4070 Basel, Switzerland; (A.B.-B.); (N.P.); (G.S.); (Y.T.); (P.B.)
| | - Yann Tessier
- Roche Pharmaceutical Research and Early Development, F. Hoffmann-La-Roche, Ltd., 4070 Basel, Switzerland; (A.B.-B.); (N.P.); (G.S.); (Y.T.); (P.B.)
| | - Paul Barrow
- Roche Pharmaceutical Research and Early Development, F. Hoffmann-La-Roche, Ltd., 4070 Basel, Switzerland; (A.B.-B.); (N.P.); (G.S.); (Y.T.); (P.B.)
| | - Steven Van Cruchten
- Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, 2610 Wilrijk, Belgium; (A.V.); (M.A.); (L.B.); (C.B.); (C.V.G.)
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17
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Schmidt S, Gallego SF, Zelnik ID, Kovalchuk S, Albæk N, Sprenger RR, Øverup C, Pewzner-Jung Y, Futerman AH, Lindholm MW, Jensen ON, Ejsing CS. Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death. Mol Ther 2021; 30:1661-1674. [PMID: 34400330 PMCID: PMC9077316 DOI: 10.1016/j.ymthe.2021.08.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/26/2021] [Accepted: 08/08/2021] [Indexed: 12/15/2022] Open
Abstract
Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders.
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Affiliation(s)
- Steffen Schmidt
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Sandra F Gallego
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Iris Daphne Zelnik
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Sergey Kovalchuk
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Nanna Albæk
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Richard R Sprenger
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Charlotte Øverup
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Yael Pewzner-Jung
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Anthony H Futerman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Marie W Lindholm
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Ole N Jensen
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Christer S Ejsing
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
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18
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Nieskens TTG, Magnusson O, Andersson P, Söderberg M, Persson M, Sjögren AK. Nephrotoxic antisense oligonucleotide SPC5001 induces kidney injury biomarkers in a proximal tubule-on-a-chip. Arch Toxicol 2021; 95:2123-2136. [PMID: 33961089 DOI: 10.1007/s00204-021-03062-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 04/28/2021] [Indexed: 01/02/2023]
Abstract
Antisense oligonucleotides (ASOs) are a promising therapeutic modality. However, failure to predict acute kidney injury induced by SPC5001 ASO observed in a clinical trial suggests the need for additional preclinical models to complement the preceding animal toxicity studies. To explore the utility of in vitro systems in this space, we evaluated the induction of nephrotoxicity and kidney injury biomarkers by SPC5001 in human renal proximal tubule epithelial cells (HRPTEC), cultured in 2D, and in a recently developed kidney proximal tubule-on-a-chip. 2D HRPTEC cultures were exposed to the nephrotoxic ASO SPC5001 or the safe control ASO 556089 (0.16-40 µM) for up to 72 h, targeting PCSK9 and MALAT1, respectively. Both ASOs induced a concentration-dependent downregulation of their respective mRNA targets but cytotoxicity (determined by LDH activity) was not observed at any concentration. Next, chip-cultured HRPTEC were exposed to SPC5001 (0.5 and 5 µM) and 556089 (1 and 10 µM) for 48 h to confirm downregulation of their respective target transcripts, with 74.1 ± 5.2% for SPC5001 (5 µM) and 79.4 ± 0.8% for 556089 (10 µM). During extended exposure for up to 20 consecutive days, only SPC5001 induced cytotoxicity (at the higher concentration; 5 µM), as evaluated by LDH in the perfusate medium. Moreover, perfusate levels of biomarkers KIM-1, NGAL, clusterin, osteopontin and VEGF increased 2.5 ± 0.2-fold, 3.9 ± 0.9-fold, 2.3 ± 0.6-fold, 3.9 ± 1.7-fold and 1.9 ± 0.4-fold respectively, in response to SPC5001, generating distinct time-dependent profiles. In conclusion, target downregulation, cytotoxicity and kidney injury biomarkers were induced by the clinically nephrotoxic ASO SPC5001, demonstrating the translational potential of this kidney on-a-chip.
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Affiliation(s)
- Tom T G Nieskens
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 43150, Mölndal, Sweden
| | - Otto Magnusson
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 43150, Mölndal, Sweden
| | - Patrik Andersson
- R&I Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Magnus Söderberg
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 43150, Mölndal, Sweden
| | - Mikael Persson
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 43150, Mölndal, Sweden
| | - Anna-Karin Sjögren
- CVRM Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Pepparedsleden 1, 43150, Mölndal, Sweden.
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19
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Valanti EK, Dalakoura-Karagkouni K, Siasos G, Kardassis D, Eliopoulos AG, Sanoudou D. Advances in biological therapies for dyslipidemias and atherosclerosis. Metabolism 2021; 116:154461. [PMID: 33290761 DOI: 10.1016/j.metabol.2020.154461] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/22/2022]
Abstract
Atherosclerosis is a multifactorial disease influenced by genetics, lifestyle and environmental factors. Despite therapeutic advances that reduce the risk of cardiovascular events, atherosclerosis-related diseases remain the leading cause of mortality worldwide. Precise targeting of genes involved in lipoprotein metabolism is an emerging approach for atherosclerosis prevention and treatment. This article focuses on the latest developments, clinical potential and current challenges of monoclonal antibodies, vaccines and genome/transcriptome modification strategies, including antisense oligonucleotides, genome/base editing and gene therapy. Multiple lipid lowering biological therapies have already been approved by the FDA with impressive results to date, while many more promising targets are being pursued in clinical trials or pre-clinical animal models.
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Affiliation(s)
- Eftaxia-Konstantina Valanti
- 4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, 'Attikon' Hospital, Medical School, National and Kapodistrian University of Athens, Greece; Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Gerasimos Siasos
- First Department of Cardiology, Hippokration Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitris Kardassis
- Laboratory of Biochemistry, University of Crete Medical School Heraklion, Greece; Division of Gene Regulation and Genomics, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Greece
| | - Aristides G Eliopoulos
- Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Despina Sanoudou
- 4th Department of Internal Medicine, Clinical Genomics and Pharmacogenomics Unit, 'Attikon' Hospital, Medical School, National and Kapodistrian University of Athens, Greece; Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Greece; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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20
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Scharner J, Aznarez I. Clinical Applications of Single-Stranded Oligonucleotides: Current Landscape of Approved and In-Development Therapeutics. Mol Ther 2020; 29:540-554. [PMID: 33359792 PMCID: PMC7854307 DOI: 10.1016/j.ymthe.2020.12.022] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 11/19/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023] Open
Abstract
Single-stranded oligonucleotides have been explored as a therapeutic modality for more than 20 years. Only during the last 5 years have single-stranded oligonucleotides become a modality of choice in the fields of precision medicine and targeted therapeutics. Recently, there have been a number of development efforts involving this modality that have led to treatments for genetic diseases that were once untreatable. This review highlights key applications of single-stranded oligonucleotides that function in a sequence-dependent manner when applied to modulate precursor (pre-)mRNA splicing, gene expression, and immune pathways. These applications have been used to address diseases that range from neurological to muscular to metabolic, as well as to develop vaccines. The wide range of applications denotes the versatility of single-stranded oligonucleotides as a robust therapeutic platform. The focus of this review is centered on approved single-stranded oligonucleotide therapies and the evolution of oligonucleotide therapeutics into novel applications currently in clinical development.
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21
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From methylene bridged diindole to carbonyl linked benzimidazoleindole: Development of potent and metabolically stable PCSK9 modulators. Eur J Med Chem 2020; 206:112678. [PMID: 32823006 DOI: 10.1016/j.ejmech.2020.112678] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/16/2020] [Accepted: 07/18/2020] [Indexed: 12/29/2022]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently validated therapeutic target for lowering low-density lipoprotein cholesterol (LDL-C). Through phenotypic screening, we previously discovered a class of small-molecules with a 2,3'-diindolymethane (DIM) skeleton that can decrease the expression of PCSK9. But these compounds have low potency and low metabolically stability. After performing structure-activity relationship (SAR) optimization by nitrogen scan, deuterium substitution and fluorine scan, we identified a series of much more potent and metabolically stable PCSK9 modulators. A preliminary in vivo pharmacokinetic study was performed for representative analogues difluorodiindolyketone (DFDIK) 12 and difluorobenzoimidazolylindolylketone (DFBIIK-1) 13. The in vitro metabolic stability correlate well with the in vivo data. The most potent compound 21 has the EC50 of 0.15 nM. Our SAR studies also indicated that the NH on the indole ring of 21 can tolerate more function groups, which may facilitate the mechanism of action studies and also allow further improvement of the pharmacological properties.
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22
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Sandelius Å, Basak J, Hölttä M, Sultana S, Hyberg G, Wilson A, Andersson P, Söderberg M. Urinary Kidney Biomarker Panel Detects Preclinical Antisense Oligonucleotide-Induced Tubular Toxicity. Toxicol Pathol 2020; 48:981-993. [PMID: 33084520 DOI: 10.1177/0192623320964391] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Sensitive kidney safety assessment is important for successful drug development in both preclinical and clinical stages. The Food and Drug Administration recently qualified a composite measure of 6 urine creatinine-normalized biomarkers, such as clusterin, cystatin C, kidney injury molecule 1 (KIM-1), N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin, for monitoring kidney toxicity in early clinical trials. The qualification was based on small molecule drugs in humans, and the full panel has not been assessed in other species or for other drug modalities. This study evaluated the effects on these biomarkers for a constrained ethyl antisense oligonucleotide (tool ASO) with demonstrated kidney toxicity in mice compared to a control ASO of the same chemistry. Dosing 50 mg/kg of the tool ASO resulted in mild proximal tubular pathology and elevations in KIM-1, clusterin, NGAL, and cystatin C. A lower dose resulted in milder histopathology and lower biomarker increases. Unexpectedly, the control ASO induced mild elevations in KIM-1, NGAL, and cystatin C, despite the lack of pathology. Both KIM-1 and clusterin were most closely associated with kidney pathology and increased with the severity of injury. Altogether, our data suggest that a biomarker panel is a sensitive tool for the detection of preclinical ASO-induced kidney pathology.
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Affiliation(s)
- Åsa Sandelius
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, 128698AstraZeneca R&D, Gothenburg, Sweden
| | - Jayati Basak
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, 128698AstraZeneca R&D, Gothenburg, Sweden
| | - Mikko Hölttä
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, 128698AstraZeneca R&D, Gothenburg, Sweden
| | - Stefan Sultana
- Patient Safety Center of Excellence, Chief Medical Office, BioPharmaceuticals 468087R&D, AstraZeneca, Cambridge, United Kingdom
| | - Gina Hyberg
- Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, 128698R&D, AstraZeneca, Gothenburg, Sweden
| | - Amanda Wilson
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, 128698AstraZeneca R&D, Gothenburg, Sweden
| | - Patrik Andersson
- Respiratory and Immunology Safety, Clinical Pharmacology and Safety Sciences, 128698R&D, AstraZeneca, Gothenburg, Sweden
| | - Magnus Söderberg
- Cardiovascular, Renal and Metabolism Safety, Clinical Pharmacology and Safety Sciences, 128698R&D, AstraZeneca, Gothenburg, Sweden
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23
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Low cholesterol syndrome and drug development. Curr Opin Cardiol 2020; 35:423-427. [PMID: 32452920 DOI: 10.1097/hco.0000000000000745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Low cholesterol syndromes were considered curiosities. The present article reviews some hypolipidaemic disorders and the drugs developed from the insights they provided. RECENT FINDINGS Abetalipopoproteinaemia and hypobetalipoproteinaemia are associated with low cholesterol concentrations and caused by mutations in apolipoprotein (apo) B or microsomal transfer protein. This led to the development of mipomersen and lomitapide which are used to treat homozygous familial hypercholesterolaemia. Mutations in proprotein convertase subtilisin kexin-9 (PCSK9) can cause either high or low cholesterol. Loss of function PCSK9 mutations prompted the development of antibody therapies to PCSK9 which are now widely used to treat hypercholesterolaemia. Mutations in apolipoprotein C-3 and angiopoietin-like protein 3 (ANGPTL3) cause hypolipoproteinaemia and reduced triglycerides. Antisense therapies to apolipoprotein C-3 and antibodies to ANGPTL3 are in development to treat familial chylomicronaemia syndrome. Activating mutations in apoA-1 result in hyper-functioning high-density lipoprotein (HDL) and suggest that modifying HDL turnover may reduce cardiovascular disease (CVD) risk. SUMMARY Orphan lipid disorders have provided insights into mechanisms involved in lowering cholesterol levels and the potential safety and efficacy of interventional processes. They have been not only enabled development of drugs to treat rare lipid disorders but also those finding wider use in general lowering of CVD risk.
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Regions of conformational flexibility in the proprotein convertase PCSK9 and design of antagonists for LDL cholesterol lowering. Biochem Soc Trans 2020; 48:1323-1336. [DOI: 10.1042/bst20190672] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/08/2020] [Accepted: 07/20/2020] [Indexed: 12/29/2022]
Abstract
The proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma LDL cholesterol levels by binding to the liver LDL receptor (LDLR) and promoting its degradation. Therefore, PCSK9 has become a compelling new therapeutic target for lipid lowering and the prevention of cardiovascular disease. PCSK9 contains two regions of conformational flexibility, the N-terminal regions of the prodomain and of the catalytic domain. The recognition that the latter region, the so-called P′ helix, is able to transition from an α-helical to a disordered state gave rise to new strategies to develop small molecule inhibitors of PCSK9 for lipid lowering. In the ordered state the P′ helix is buried in a groove of the PCSK9 catalytic domain located next to the main LDLR binding site. The transition to a disordered state leaves the groove site vacated and accessible for compounds to antagonize LDLR binding. By use of a groove-directed phage display strategy we were able to identify several groove-binding peptides. Based on structural information of PCSK9-peptide complexes, a minimized groove-binding peptide was generated and utilized as an anchor to extend towards the adjacent main LDLR binding site, either by use of a phage-displayed peptide extension library, or by appending organic moieties to yield organo-peptides. Both strategies led to antagonists with pharmacologic activities in cell-based assays. The intricate bipartite mechanism of the potent organo-peptide inhibitors was revealed by structural studies, showing that the core peptide occupies the N-terminal groove, while the organic moiety interacts with the LDLR binding site to create antagonism. These findings validate the PCSK9 groove as an attractive target site and should inspire the development of a new class of small molecule antagonists of PCSK9.
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Das S, Shah R, Dimmeler S, Freedman JE, Holley C, Lee JM, Moore K, Musunuru K, Wang DZ, Xiao J, Yin KJ. Noncoding RNAs in Cardiovascular Disease: Current Knowledge, Tools and Technologies for Investigation, and Future Directions: A Scientific Statement From the American Heart Association. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2020; 13:e000062. [PMID: 32812806 DOI: 10.1161/hcg.0000000000000062] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The discovery that much of the non-protein-coding genome is transcribed and plays a diverse functional role in fundamental cellular processes has led to an explosion in the development of tools and technologies to investigate the role of these noncoding RNAs in cardiovascular health. Furthermore, identifying noncoding RNAs for targeted therapeutics to treat cardiovascular disease is an emerging area of research. The purpose of this statement is to review existing literature, offer guidance on tools and technologies currently available to study noncoding RNAs, and identify areas of unmet need. METHODS The writing group used systematic literature reviews (including MEDLINE, Web of Science through 2018), expert opinion/statements, analyses of databases and computational tools/algorithms, and review of current clinical trials to provide a broad consensus on the current state of the art in noncoding RNA in cardiovascular disease. RESULTS Significant progress has been made since the initial studies focusing on the role of miRNAs (microRNAs) in cardiovascular development and disease. Notably, recent progress on understanding the role of novel types of noncoding small RNAs such as snoRNAs (small nucleolar RNAs), tRNA (transfer RNA) fragments, and Y-RNAs in cellular processes has revealed a noncanonical function for many of these molecules. Similarly, the identification of long noncoding RNAs that appear to play an important role in cardiovascular disease processes, coupled with the development of tools to characterize their interacting partners, has led to significant mechanistic insight. Finally, recent work has characterized the unique role of extracellular RNAs in mediating intercellular communication and their potential role as biomarkers. CONCLUSIONS The rapid expansion of tools and pipelines for isolating, measuring, and annotating these entities suggests that caution in interpreting results is warranted until these methodologies are rigorously validated. Most investigators have focused on investigating the functional role of single RNA entities, but studies suggest complex interaction between different RNA molecules. The use of network approaches and advanced computational tools to understand the interaction of different noncoding RNA species to mediate a particular phenotype may be required to fully comprehend the function of noncoding RNAs in mediating disease phenotypes.
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MESH Headings
- American Heart Association
- Biomarkers/metabolism
- Cardiovascular Diseases/genetics
- Cardiovascular Diseases/pathology
- Humans
- MicroRNAs/chemistry
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA, Long Noncoding/chemistry
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- RNA, Small Nucleolar/chemistry
- RNA, Small Nucleolar/genetics
- RNA, Small Nucleolar/metabolism
- RNA, Transfer/chemistry
- RNA, Transfer/genetics
- RNA, Transfer/metabolism
- RNA, Untranslated/chemistry
- RNA, Untranslated/genetics
- RNA, Untranslated/metabolism
- United States
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Hu B, Boakye‐Yiadom KO, Yu W, Yuan Z, Ho W, Xu X, Zhang X. Nanomedicine Approaches for Advanced Diagnosis and Treatment of Atherosclerosis and Related Ischemic Diseases. Adv Healthc Mater 2020; 9:e2000336. [PMID: 32597562 DOI: 10.1002/adhm.202000336] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/30/2020] [Indexed: 12/16/2022]
Abstract
Cardiovascular diseases (CVDs) remain one of the major causes of mortality worldwide. In response to this and other worldwide health epidemics, nanomedicine has emerged as a rapidly evolving discipline that involves the development of innovative nanomaterials and nanotechnologies and their applications in therapy and diagnosis. Nanomedicine presents unique advantages over conventional medicines due to the superior properties intrinsic to nanoscopic therapies. Once used mainly for cancer therapies, recently, tremendous progress has been made in nanomedicine that has led to an overall improvement in the treatment and diagnosis of CVDs. This review elucidates the pathophysiology and potential targets of atherosclerosis and associated ischemic diseases. It may be fruitful to pursue future work in the nanomedicine-mediated treatment of CVDs based on these targets. A comprehensive overview is then provided featuring the latest preclinical and clinical outcomes in cardiovascular imaging, biomarker detection, tissue engineering, and nanoscale delivery, with specific emphasis on nanoparticles, nanostructured scaffolds, and nanosensors. Finally, the challenges and opportunities regarding the future development and clinical translation of nanomedicine in related fields are discussed. Overall, this review aims to provide a deep and thorough understanding of the design, application, and future development of nanomedicine for atherosclerosis and related ischemic diseases.
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Affiliation(s)
- Bin Hu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of PharmacyShanghai Jiao Tong University 800 Dongchuan Road Shanghai 200240 P. R. China
| | - Kofi Oti Boakye‐Yiadom
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of PharmacyShanghai Jiao Tong University 800 Dongchuan Road Shanghai 200240 P. R. China
| | - Wei Yu
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of PharmacyShanghai Jiao Tong University 800 Dongchuan Road Shanghai 200240 P. R. China
| | - Zi‐Wei Yuan
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of PharmacyShanghai Jiao Tong University 800 Dongchuan Road Shanghai 200240 P. R. China
| | - William Ho
- Department of Chemical and Materials EngineeringNew Jersey Institute of Technology Newark NJ 07102 USA
| | - Xiaoyang Xu
- Department of Chemical and Materials EngineeringNew Jersey Institute of Technology Newark NJ 07102 USA
| | - Xue‐Qing Zhang
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, and School of PharmacyShanghai Jiao Tong University 800 Dongchuan Road Shanghai 200240 P. R. China
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Malvandi AM, Canclini L, Alliaj A, Magni P, Zambon A, Catapano AL. Progress and prospects of biological approaches targeting PCSK9 for cholesterol-lowering, from molecular mechanism to clinical efficacy. Expert Opin Biol Ther 2020; 20:1477-1489. [PMID: 32715821 DOI: 10.1080/14712598.2020.1801628] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Cardiovascular disorders are one of the leading causes of mortality and morbidity worldwide. Recent advances showed a promising role of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a critical player in regulating plasma LDL levels and lipid metabolism. AREAS COVERED This review addresses the molecular functions of PCSK9 with a vision on the clinical progress of utilizing monoclonal antibodies and other biological approaches to block PCSK9 activity. The successful clinical trials with monoclonal antibodies are reviewed. Recent advances in (pre)clinical trials of other biological approaches, such as small interfering RNAs, are also discussed. EXPERT OPINION Discovery of PCSK9 and clinical use of its inhibitors to manage lipid metabolism is a step forward in hypolipidaemic therapy. A better understanding of the molecular activity of PCSK9 can help to identify new approaches in the inhibition of PCSK9 expression/activity. Whether if PCSK9 plays a role in other cardiometabolic conditions may provide grounds for further development of therapies.
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Affiliation(s)
| | - Laura Canclini
- IRCCS Multimedica , Milan, Italy.,Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano , Milan, Italy
| | | | - Paolo Magni
- IRCCS Multimedica , Milan, Italy.,Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano , Milan, Italy
| | - Alberto Zambon
- IRCCS Multimedica , Milan, Italy.,Department of Medicine, Università degli Studi di Padova , Padua, Italy
| | - Alberico Luigi Catapano
- IRCCS Multimedica , Milan, Italy.,Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano , Milan, Italy
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Abstract
BACKGROUND Despite advances in the development of lipid-lowering therapies, clinical trials have shown that a significant residual risk of cardiovascular disease persists. Specifically, new drugs are needed for non-responding or statin-intolerant subjects or patients considered at very high risk for cardiovascular events even though are already on treatment with the best standard of care. RESULTS AND CONCLUSIONS Besides, genetic and epidemiological studies and Mendelian randomization analyses have strengthened the linear correlation between the concentration of low-density lipoprotein cholesterol (LDL-C) and the incidence of cardiovascular events and highlighted various novel therapeutic targets. This review describes the novel strategies to reduce the levels of LDL-C, non-HDL-C, triglyceride, apolipoprotein B, and Lp(a), focusing on those developed using biotechnology-based strategies.
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29
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Kim EJ, Wierzbicki AS. The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease. Ther Adv Chronic Dis 2020; 11:2040622320924569. [PMID: 32537117 PMCID: PMC7268157 DOI: 10.1177/2040622320924569] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/15/2020] [Indexed: 12/22/2022] Open
Abstract
A consensus has formed based on epidemiological studies and clinical trials that intervention to reduce low density lipoprotein cholesterol (LDL-C) will reduce cardiovascular disease (CVD) events. This has progressively reduced the thresholds for intervention and targets for treatment. Whist statins are sufficient for many people in primary prevention, they only partially achieve the newer targets of secondary prevention for established CVD. Increasing use of statins has highlighted that 1–2% cannot tolerate these drugs. Other cholesterol-lowering drugs such as ezetimibe add to the benefits of statins but have limited efficacy. The discovery of activating mutations in proprotein convertase subtilisin kexin-9 (PCSK9) as a cause of familial hypercholesterolaemia while inactivating mutations lower LDL-C led to the idea to develop PCSK9 inhibitors as drugs. This article reviews the history of lipid-lowering therapies, the discovery of PCSK9 and the development of PCSK9 inhibitors. It reviews the key trials of the current antibody-based drugs and how these have influenced new guidelines. It also reviews the controversy caused by their cost and the increasing application of health economics to determine the optimum strategy for implementation of novel therapeutic pathways and surveys other options for targeting PCSK9 as well as other LDL-C lowering compounds in late development.
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Affiliation(s)
- Eun Ji Kim
- Department of Metabolic Medicine/Chemical Pathology, Guy's & St Thomas' Hospitals, London, UK
| | - Anthony S Wierzbicki
- Department of Chemical Pathology, St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK
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30
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Kloska A, Malinowska M, Gabig-Cimińska M, Jakóbkiewicz-Banecka J. Lipids and Lipid Mediators Associated with the Risk and Pathology of Ischemic Stroke. Int J Mol Sci 2020; 21:ijms21103618. [PMID: 32443889 PMCID: PMC7279232 DOI: 10.3390/ijms21103618] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/18/2020] [Accepted: 05/19/2020] [Indexed: 12/19/2022] Open
Abstract
Stroke is a severe neurological disorder in humans that results from an interruption of the blood supply to the brain. Worldwide, stoke affects over 100 million people each year and is the second largest contributor to disability. Dyslipidemia is a modifiable risk factor for stroke that is associated with an increased risk of the disease. Traditional and non-traditional lipid measures are proposed as biomarkers for the better detection of subclinical disease. In the central nervous system, lipids and lipid mediators are essential to sustain the normal brain tissue structure and function. Pathways leading to post-stroke brain deterioration include the metabolism of polyunsaturated fatty acids. A variety of lipid mediators are generated from fatty acids and these molecules may have either neuroprotective or neurodegenerative effects on the post-stroke brain tissue; therefore, they largely contribute to the outcome and recovery from stroke. In this review, we provide an overview of serum lipids associated with the risk of ischemic stroke. We also discuss the role of lipid mediators, with particular emphasis on eicosanoids, in the pathology of ischemic stroke. Finally, we summarize the latest research on potential targets in lipid metabolic pathways for ischemic stroke treatment and on the development of new stroke risk biomarkers for use in clinical practice.
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Affiliation(s)
- Anna Kloska
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (A.K.); (M.M.)
| | - Marcelina Malinowska
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (A.K.); (M.M.)
| | - Magdalena Gabig-Cimińska
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (A.K.); (M.M.)
- Laboratory of Molecular Biology, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Kładki 24, 80-822 Gdańsk, Poland
- Correspondence: (M.G.-C.); (J.J.-B.); Tel.: +48-585-236-046 (M.G.-C.); +48-585-236-043 (J.J.-B.)
| | - Joanna Jakóbkiewicz-Banecka
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (A.K.); (M.M.)
- Correspondence: (M.G.-C.); (J.J.-B.); Tel.: +48-585-236-046 (M.G.-C.); +48-585-236-043 (J.J.-B.)
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31
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A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove. Bioorg Med Chem 2020; 28:115344. [DOI: 10.1016/j.bmc.2020.115344] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 01/17/2020] [Accepted: 01/23/2020] [Indexed: 12/11/2022]
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32
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Burdick DJ, Skelton NJ, Ultsch M, Beresini MH, Eigenbrot C, Li W, Zhang Y, Nguyen H, Kong-Beltran M, Quinn JG, Kirchhofer D. Design of Organo-Peptides As Bipartite PCSK9 Antagonists. ACS Chem Biol 2020; 15:425-436. [PMID: 31962046 DOI: 10.1021/acschembio.9b00899] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Proprotein convertase subtilisin/kexin 9 (PCSK9) has become an important therapeutic target for lipid lowering, since it regulates low-density lipoprotein cholesterol (LDL-c) levels by binding to liver LDL receptors (LDLR) and effecting their intracellular degradation. However, the development of small molecule inhibitors is hampered by the lack of attractive PCSK9 target sites. We recently discovered helical peptides that are able to bind to a cryptic groove site on PCSK9, which is situated in proximity to the main LDLR binding site. Here, we designed potent bipartite PCSK9 inhibitors by appending organic moieties to a helical groove-binding peptide to reach a hydrophobic pocket in the proximal LDLR binding region. The ultimately designed 1-amino-4-phenylcyclohexane-1-carbonyl extension improved the peptide affinity by >100-fold, yielding organo-peptide antagonists that potently inhibited PCSK9 binding to LDLR and preserved cellular LDLR. These new bipartite antagonists have reduced mass and improved potency compared to the first-generation peptide antagonists, further validating the PCSK9 groove as a viable therapeutic target site.
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Abstract
PURPOSE OF REVIEW Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis. RECENT FINDINGS RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.
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Affiliation(s)
- Petri Mäkinen
- A.I. Virtanen Institute, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Anna-Kaisa Ruotsalainen
- A.I. Virtanen Institute, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland
| | - Seppo Ylä-Herttuala
- A.I. Virtanen Institute, University of Eastern Finland, Neulaniementie 2, P.O. Box 1627, 70211, Kuopio, Finland.
- Heart Center and Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.
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Panagiotopoulou O, Chiesa ST, Tousoulis D, Charakida M. Dyslipidaemias and Cardiovascular Disease: Focus on the Role of PCSK9 Inhibitors. Curr Med Chem 2020; 27:4494-4521. [PMID: 31453780 DOI: 10.2174/0929867326666190827151012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 12/23/2018] [Accepted: 01/15/2019] [Indexed: 12/19/2022]
Abstract
Genetic, experimental and clinical studies have consistently confirmed that inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) can result in significant lowering of LDL-C and two fully human PCSK9 monoclonal antibodies have received regulatory approval for use in highrisk patients. Co-administration of PCSK9 with statins has resulted in extremely low LDL-C levels with excellent short-term safety profiles. While results from Phase III clinical trials provided significant evidence about the role of PCSK9 inhibitors in reducing cardiovascular event rates, their impact on mortality remains less clear. PCSK9 inhibitor therapy can be considered for high-risk patients who are likely to experience significant cardiovascular risk reduction.
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Affiliation(s)
- Olga Panagiotopoulou
- School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor, Lambeth Wing St. Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Scott T Chiesa
- UCL Institute of Cardiovascular Sciences, London, United Kingdom
| | | | - Marietta Charakida
- School of Biomedical Engineering and Imaging Sciences, King's College London, 4th Floor, Lambeth Wing St. Thomas' Hospital, London SE1 7EH, United Kingdom
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35
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Inclisiran-New hope in the management of lipid disorders? J Clin Lipidol 2019; 14:16-27. [PMID: 31879073 DOI: 10.1016/j.jacl.2019.11.001] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 10/16/2019] [Accepted: 11/05/2019] [Indexed: 11/23/2022]
Abstract
Drugs reducing plasma concentrations of apolipoprotein B-containing lipoproteins have been demonstrated to reduce the risk of cardiovascular disease (CVD) in both primary and secondary prevention. Despite the demonstrated efficacy of statins and ezetimibe on low-density lipoprotein (LDL) concentration and long-term CVD risk, a large number of patients do not achieve their therapeutic goals. The introduction of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was a milestone in the treatment of lipid disorders, as their administration leads to unprecedentedly low LDL cholesterol concentrations. Inclisiran represents an entirely new mechanism of PSCK9 protein inhibition in hepatocytes, targeting the messenger RNA for PCSK9. Its administration is necessary only every 3 to 6 months, which is an essential advantage over statin and monoclonal antibody therapy. The infrequent administration regimen can increase the number of patients who maintain their therapeutic goals, especially in patients struggling to comply with daily or biweekly pharmacotherapy. Preclinical studies and Phase I and Phase II clinical trials of inclisiran have demonstrated its tolerability and efficacy in promoting long-term reduction of both PCSK9 protein and LDL cholesterol. The efficacy and safety of inclisiran will continue to be assessed in ongoing and forthcoming trials on larger patient groups. If the results of these trials reflect previously published data, they will add further evidence that inclisiran might be a revolutionary new tool in the pharmacologic management of plasma lipids. This review summarizes the currently available literature data on inclisiran with respect to its mechanism of action, effectiveness, and safety as a lipid-lowering drug for CVD prevention.
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36
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Yamamoto T, Sawamura M, Terada C, Kashiwada K, Wada F, Yamayoshi A, Obika S, Harada-Shiba M. Effect of modular conjugation strategy for N-acetylgalactosamine-targeted antisense oligonucleotides. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 2019; 39:109-118. [PMID: 31617782 DOI: 10.1080/15257770.2019.1677911] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The asialoglycoprotein receptor (ASGPr) and N-acetylgalactosamine (GalNAc) is one of the most reliable receptor-ligand combinations for delivering antisense oligonucleotides (ASOs) to the liver. Here, we show that a modular GalNAc conjugation strategy allows us to reinforce the activity of the parent, naked 2',4'-BNA/LNA gapmer targeting apolipoprotein B. The conjugation partly reduced a possible hepatotoxicity of the parent ASO. The structure-activity study revealed the significance of the metabolic susceptibility of the GalNAc moiety to nucleolytic cleavage that results in exposure of the parent gapmer. The broad usefulness of our delivery strategy of ASOs to the liver has been demonstrated.
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Affiliation(s)
- Tsuyoshi Yamamoto
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Motoki Sawamura
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Chisato Terada
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Koki Kashiwada
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Fumito Wada
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
| | - Asako Yamayoshi
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Satoshi Obika
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Mariko Harada-Shiba
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
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37
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Macchi C, Sirtori CR, Corsini A, Santos RD, Watts GF, Ruscica M. A new dawn for managing dyslipidemias: The era of rna-based therapies. Pharmacol Res 2019; 150:104413. [PMID: 31449975 DOI: 10.1016/j.phrs.2019.104413] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/08/2019] [Accepted: 08/22/2019] [Indexed: 12/24/2022]
Abstract
The high occurrence of atherosclerotic cardiovascular disease (ASCVD) events is still a major public health issue. Although a major determinant of ASCVD event reduction is the absolute change of low-density lipoprotein-cholesterol (LDL-C), considerable residual risk remains and new therapeutic options are required, in particular, to address triglyceride-rich lipoproteins and lipoprotein(a) [Lp(a)]. In the era of Genome Wide Association Studies and Mendelian Randomization analyses aimed at increasing the understanding of the pathophysiology of ASCVD, RNA-based therapies may offer more effective treatment options. The advantage of oligonucleotide-based treatments is that drug candidates are targeted at highly specific regions of RNA that code for proteins that in turn regulate lipid and lipoprotein metabolism. For LDL-C lowering, the use of inclisiran - a silencing RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis - has the advantage that a single s.c. injection lowers LDL-C for up to 6 months. In familial hypercholesterolemia, the use of the antisense oligonucleotide (ASO) mipomersen, targeting apolipoprotein (apoB) to reduce LDL-C, has been a valuable therapeutic approach, despite unquestionable safety concerns. The availability of specific ASOs lowering Lp(a) levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, Volanesorsen (APOC3) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.
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Affiliation(s)
- C Macchi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - C R Sirtori
- Dyslipidemia Center, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - A Corsini
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy; IRCCS Multimedica, Milan, Italy
| | - R D Santos
- Lipid Clinic, Heart Institute (InCor), University of Sao Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - G F Watts
- School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia; Lipid Disorders Clinic, Cardiometabolic Services, Department of Cardiology, Royal Perth Hospital, Australia.
| | - M Ruscica
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
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Abstract
PURPOSE OF REVIEW A number of novel trials have assessed the efficacy of new lipid-lowering therapies in cardiovascular disease (CVD). RECENT FINDINGS Proprotein convertase subtilisin kexin-9 inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 50-55%. A CVD outcome trial in patients with acute coronary syndromes with evolocumab achieved a LDL-C of 0.8 mmol/l (31 mg/dl) and a 20% relative risk reduction in CVD events in 2.2 years. Cholesterol ester transfer protein inhibitors raise high-density lipoprotein cholesterol and can lower LDL-C. Anacetrapib reduced coronary artery disease events by 7%, but not wider composite CVD outcomes, in a population with chronic CVD with pretreatment LDL-C of 1.6 mmol/l (62 mg/dl). The conflicting outcomes of cholesterol ester transfer protein inhibitor trials means these compounds are not being developed further. Trials using lipid drugs targeting inflammation have previously been generally unsuccessful, but recent data on the interleukin-1B receptor antagonist canakinumab has proven the concept of intervention on inflammation in atherosclerosis by showing a reduction in acute coronary interventions, but at the predictable cost of increased infections. SUMMARY Despite the success of proprotein convertase subtilisin kexin-9 inhibition, the ability to achieve low LDL-C with off-patent medications and the costs of novel therapies will limit their use even in high-risk patients and confine them to the highest-risk sub-groups of patients.
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39
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Zwol WV, Rimbert A, Kuivenhoven JA. The Future of Lipid-lowering Therapy. J Clin Med 2019; 8:E1085. [PMID: 31340607 PMCID: PMC6678580 DOI: 10.3390/jcm8071085] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 07/19/2019] [Accepted: 07/22/2019] [Indexed: 12/13/2022] Open
Abstract
The recent introduction of inhibitors of proprotein convertase subtilisin/kexin 9 to lower low-density lipoprotein (LDL) cholesterol on top of statins or as monotherapy is rapidly changing the landscape of treatment of atherosclerotic cardiovascular disease (ASCVD). However, existing lipid-lowering drugs have little impact on lipoprotein(a) (Lp(a)) or plasma triglycerides, two other risk factors for ASCVD. This review summarizes the evidence and the rationale to target Lp(a) and triglycerides and provides an overview of currently tested strategies to lower Lp(a), apolipoprotein C-III and angiopoietin-like protein 3. In addition, it summarizes new findings on the use of omega-3 fatty acids (OM3FA) to fight ASCVD. With the exception of OM3FA supplementation, the promise of the experimental drugs discussed here depends on the long-term safety and efficacy of monoclonal antibodies and/or antisense oligonucleotides Clinical outcome trials will ultimately prove whether these new therapeutic modalities will reduce ASCVD risk.
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Affiliation(s)
- Willemien van Zwol
- Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Centre Groningen, 9713 Groningen, The Netherlands
| | - Antoine Rimbert
- Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Centre Groningen, 9713 Groningen, The Netherlands
| | - Jan Albert Kuivenhoven
- Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Centre Groningen, 9713 Groningen, The Netherlands.
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40
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Abstract
Cardiovascular disease is the major cause of death globally, with hypercholesterolemia being an important risk factor. The PCSK9 represents an attractive therapeutic target for hypercholesterolemia treatment and is currently in the spotlight of the scientific community. After autocatalytic activation in the hepatocyte endoplasmic reticulum, this convertase binds to the LDLR and channels it to the degradation pathway. This review gives an overview on the latest developments in the inhibition of PCSK9, including disruption of the protein-protein interaction (PPI) between PCSK9 and LDLR by peptidomimetics, adnectins and monoclonal antibodies and the suppression of PCSK9 expression by small molecules, siRNA and genome editing techniques. In addition, we discuss alternative approaches, such as anti-PCSK9 active vaccination and heparin mimetics.
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41
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Fuschi P, Maimone B, Gaetano C, Martelli F. Noncoding RNAs in the Vascular System Response to Oxidative Stress. Antioxid Redox Signal 2019; 30:992-1010. [PMID: 28683564 DOI: 10.1089/ars.2017.7229] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Redox homeostasis plays a pivotal role in vascular cell function and its imbalance has a causal role in a variety of vascular diseases. Accordingly, the response of mammalian cells to redox cues requires precise transcriptional and post-transcriptional modulation of gene expression patterns. Recent Advances: Mounting evidence shows that nonprotein-coding RNAs (ncRNAs) are important for the functional regulation of most, if not all, cellular processes and tissues. Not surprisingly, a prominent role of ncRNAs has been identified also in the vascular system response to oxidative stress. CRITICAL ISSUES The highly heterogeneous family of ncRNAs has been divided into several groups. In this article we focus on two classes of regulatory ncRNAs: microRNAs and long ncRNAs (lncRNAs). Although knowledge in many circumstances, and especially for lncRNAs, is still fragmentary, ncRNAs are clinically interesting because of their diagnostic and therapeutic potential. We outline ncRNAs that are regulated by oxidative stress as well as ncRNAs that modulate reactive oxygen species production and scavenging. More importantly, we describe the role of these ncRNAs in vascular physiopathology and specifically in disease conditions wherein oxidative stress plays a crucial role, such as hypoxia and ischemia, ischemia reperfusion, inflammation, diabetes mellitus, and atherosclerosis. FUTURE DIRECTIONS The therapeutic potential of ncRNAs in vascular diseases and in redox homeostasis is discussed.
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Affiliation(s)
- Paola Fuschi
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Biagina Maimone
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
| | - Carlo Gaetano
- 2 Division of Cardiovascular Epigenetics, Department of Cardiology, Goethe University, Frankfurt am Main, Germany
| | - Fabio Martelli
- 1 Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy
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42
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Nishikido T, Ray KK. Non-antibody Approaches to Proprotein Convertase Subtilisin Kexin 9 Inhibition: siRNA, Antisense Oligonucleotides, Adnectins, Vaccination, and New Attempts at Small-Molecule Inhibitors Based on New Discoveries. Front Cardiovasc Med 2019; 5:199. [PMID: 30761308 PMCID: PMC6361748 DOI: 10.3389/fcvm.2018.00199] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 12/28/2018] [Indexed: 12/17/2022] Open
Abstract
Low-density lipoprotein (LDL) is one of the principal risk factors for atherosclerosis. Circulating LDL particles can penetrate into the sub-endothelial space of arterial walls. These particles undergo oxidation and promote an inflammatory response, resulting in injury to the vascular endothelial wall. Persistent elevation of LDL-cholesterol (LDL-C) is linked to the progression of fatty streaks to lipid-rich plaque and thus atherosclerosis. LDL-C is a causal factor for atherosclerotic cardiovascular disease and lowering it is beneficial across a range of conditions associated with high risk of cardiovascular events. Therefore, all guidelines-recommended initiations of statin therapy for patients at high cardiovascular risk is irrespective of LDL-C. In addition, intensive LDL-C lowering therapy with statins has been demonstrated to result in a greater reduction of cardiovascular event risk in large clinical trials. However, many high-risk patients receiving statins fail to achieve the guideline-recommended reduction in LDL-C levels in routine clinical practice. Moreover, low levels of adherence and often high rates of discontinuation demand the need for further therapies. Ezetimibe has typically been used as a complement to statins when further LDL-C reduction is required. More recently, proprotein convertase subtilisin kexin 9 (PCSK9) has emerged as a novel therapeutic target for lowering LDL-C levels, with PCSK9 inhibitors offering greater reductions than feasible through the addition of ezetimibe. PCSK9 monoclonal antibodies have been shown to not only considerably lower LDL-C levels but also cardiovascular events. However, PCSK9 monoclonal antibodies require once- or twice-monthly subcutaneous injections. Further, their manufacturing process is expensive, increasing the cost of therapy. Therefore, several non-antibody treatments to inhibit PCSK9 function are being developed as alternative approaches to monoclonal antibodies. These include gene-silencing or editing technologies, such as antisense oligonucleotides, small interfering RNA, and the clustered regularly interspaced short palindromic repeats/Cas9 platform; small-molecule inhibitors; mimetic peptides; adnectins; and vaccination. In this review, we summarize the current knowledge base on the role of PCSK9 in lipid metabolism and an overview of non-antibody approaches for PCSK9 inhibition and their limitations. The subsequent development of alternative approaches to PCSK9 inhibition may give us more affordable and convenient therapeutic options for the management of high-risk patients.
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Affiliation(s)
- Toshiyuki Nishikido
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.,Department of Cardiovascular medicine, Saga University, Saga, Japan
| | - Kausik K Ray
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom
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43
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Affiliation(s)
- Arthur A Levin
- From Research and Development, Avidity Biosciences, La Jolla, CA
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44
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Khoshnejad M, Patel A, Wojtak K, Kudchodkar SB, Humeau L, Lyssenko NN, Rader DJ, Muthumani K, Weiner DB. Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics. Mol Ther 2019; 27:188-199. [PMID: 30449662 PMCID: PMC6319316 DOI: 10.1016/j.ymthe.2018.10.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/16/2018] [Accepted: 10/25/2018] [Indexed: 01/07/2023] Open
Abstract
Elevated low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to cardiovascular heart disease (CHD), the leading cause of death worldwide. Due to severe side effects of statins, alternative treatment strategies are required for statin-intolerant patients. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown great efficacy in LDL-C reduction. Limitations for this approach include the need for multiple injections as well as increased costs associated with patient management. Here, we engineered a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9), as an alternative approach to protein-based lipid-lowering therapeutics, and we characterized its expression and activity. A single intramuscular administration of mouse daPCSK9 generated expression in vivo for over 42 days that corresponded with a substantial decrease of 28.6% in non-high-density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7 in wild-type mice. Repeated administrations of the DMAb plasmid led to increasing expression, with DMAb levels of 7.5 μg/mL at day 62. daPCSK9 therapeutics may provide a novel, simple, less frequent, cost-effective approach to reducing LDL-C, either as a stand-alone therapy or in combination with other LDL-lowering therapeutics for synergistic effect.
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Affiliation(s)
- Makan Khoshnejad
- Vaccine and Immunotherapy Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Ami Patel
- Vaccine and Immunotherapy Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Krzysztof Wojtak
- Vaccine and Immunotherapy Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Sagar B. Kudchodkar
- Vaccine and Immunotherapy Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - Laurent Humeau
- Inovio Pharmaceuticals, Inc., Plymouth Meeting, PA 19462, USA
| | - Nicholas N. Lyssenko
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Daniel J. Rader
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kar Muthumani
- Vaccine and Immunotherapy Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
| | - David B. Weiner
- Vaccine and Immunotherapy Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA,Corresponding author: David B. Weiner, Vaccine and Immunotherapy Center, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
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45
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Small molecules as inhibitors of PCSK9: Current status and future challenges. Eur J Med Chem 2018; 162:212-233. [PMID: 30448414 DOI: 10.1016/j.ejmech.2018.11.011] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/13/2018] [Accepted: 11/05/2018] [Indexed: 12/11/2022]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed.
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46
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Almuttaqi H, Udalova IA. Advances and challenges in targeting IRF5, a key regulator of inflammation. FEBS J 2018; 286:1624-1637. [PMID: 30199605 PMCID: PMC6563445 DOI: 10.1111/febs.14654] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/26/2018] [Accepted: 09/07/2018] [Indexed: 12/14/2022]
Abstract
Interferon regulatory factor 5 (IRF5) belongs to a family of transcription factors, originally implicated in antiviral responses and interferon production. However, studies conducted in different laboratories over the last decade have placed IRF5 as a central regulator of the inflammatory response. It has become clear that IRF5 contributes to the pathogenesis of many inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus. Given the role of IRF5 in physiology and disease, IRF5 represents a potential therapeutic target. However, despite a significant interest from the pharmaceutical industry, inhibitors that interfere with the IRF5 pathway remain elusive. Here, we review the advances made by various studies in targeting multiple steps of signalling leading to IRF5 activation with their therapeutic potential, and the possible complications of such strategies are discussed.
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47
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Abstract
SIGNIFICANCE To maintain homeostasis, gene expression has to be tightly regulated by complex and multiple mechanisms occurring at the epigenetic, transcriptional, and post-transcriptional levels. One crucial regulatory component is represented by long noncoding RNAs (lncRNAs), nonprotein-coding RNA species implicated in all of these levels. Thus, lncRNAs have been associated with any given process or pathway of interest in a variety of systems, including the heart. Recent Advances: Mounting evidence implicates lncRNAs in cardiovascular diseases (CVD) and progression and their presence in the blood of heart disease patients indicates that they are attractive potential biomarkers. CRITICAL ISSUES Our understanding of the regulation and molecular mechanisms of action of most lncRNAs remains rudimentary. A challenge is represented by their often low evolutionary sequence conservation that limits the use of animal models for preclinical studies. Nevertheless, a growing number of lncRNAs with an impact on heart function is rapidly accumulating. In this study, we will discuss (i) lncRNAs that control heart homeostasis and disease; (ii) concepts, approaches, and methodologies necessary to study lncRNAs in the heart; and (iii) challenges posed and opportunities presented by lncRNAs as potential therapeutic targets and biomarkers. FUTURE DIRECTIONS A deeper knowledge of the molecular mechanisms underpinning CVDs is necessary to develop more effective treatments. Further studies are needed to clarify the regulation and function of lncRNAs in the heart before they can be considered as therapeutic targets and disease biomarkers. Antioxid. Redox Signal. 29, 880-901.
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Affiliation(s)
- Simona Greco
- 1 Molecular Cardiology Laboratory, IRCCS Policlinico San Donato , Milan, Italy
| | - Antonio Salgado Somoza
- 2 Cardiovascular Research Unit, Luxembourg Institute of Health (LIH) , Luxembourg, Luxembourg
| | - Yvan Devaux
- 2 Cardiovascular Research Unit, Luxembourg Institute of Health (LIH) , Luxembourg, Luxembourg
| | - Fabio Martelli
- 1 Molecular Cardiology Laboratory, IRCCS Policlinico San Donato , Milan, Italy
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48
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De Majo F, De Windt LJ. RNA therapeutics for heart disease. Biochem Pharmacol 2018; 155:468-478. [DOI: 10.1016/j.bcp.2018.07.037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 07/25/2018] [Indexed: 12/20/2022]
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49
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Laina A, Gatsiou A, Georgiopoulos G, Stamatelopoulos K, Stellos K. RNA Therapeutics in Cardiovascular Precision Medicine. Front Physiol 2018; 9:953. [PMID: 30090066 PMCID: PMC6068259 DOI: 10.3389/fphys.2018.00953] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/28/2018] [Indexed: 12/20/2022] Open
Abstract
Since our knowledge on structure and function of messenger RNA (mRNA) has expanded from merely being an intermediate molecule between DNA and proteins to the notion that RNA is a dynamic gene regulator that can be modified and edited, RNA has become a focus of interest into developing novel therapeutic schemes. Therapeutic modulation of RNA molecules by DNA- and RNA-based therapies has broadened the scope of therapeutic targets in infectious diseases, cancer, neurodegenerative diseases and most recently in cardiovascular diseases as well. Currently, antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), and microRNAs are the most widely applied therapeutic strategies to target RNA molecules and regulate gene expression and protein production. However, a number of barriers have to be overcome including instability, inadequate binding affinity and delivery to the tissues, immunogenicity, and off-target toxicity in order for these agents to evolve into efficient drugs. As cardiovascular diseases remain the leading cause of mortality worldwide, a large number of clinical trials are under development investigating the safety and efficacy of RNA therapeutics in clinical conditions such as familial hypercholesterolemia, diabetes mellitus, hypertriglyceridemia, cardiac amyloidosis, and atrial fibrillation. In this review, we summarize the clinical trials of RNA-targeting therapies in cardiovascular disease and critically discuss the advances, the outcomes, the limitations and the future directions of RNA therapeutics in precision transcriptomic medicine.
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Affiliation(s)
- Ageliki Laina
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Aikaterini Gatsiou
- Center of Molecular Medicine, Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.,Department of Cardiology, Center of Internal Medicine, Goethe University Frankfurt, Frankfurt, Germany.,German Center of Cardiovascular Research, Rhein-Main Partner Site, Frankfurt, Germany
| | - Georgios Georgiopoulos
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Kimon Stamatelopoulos
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Stellos
- Center of Molecular Medicine, Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt, Germany.,Department of Cardiology, Center of Internal Medicine, Goethe University Frankfurt, Frankfurt, Germany.,German Center of Cardiovascular Research, Rhein-Main Partner Site, Frankfurt, Germany.,Cardiovascular Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.,Department of Cardiology, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
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50
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Sathiyakumar V, Kapoor K, Jones SR, Banach M, Martin SS, Toth PP. Novel Therapeutic Targets for Managing Dyslipidemia. Trends Pharmacol Sci 2018; 39:733-747. [PMID: 29970260 DOI: 10.1016/j.tips.2018.06.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 05/31/2018] [Accepted: 06/01/2018] [Indexed: 11/16/2022]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations. Therapeutic modulation of dyslipidemia by inhibiting 3'-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is standard practice throughout the world. However, based on findings from Mendelian studies and genetic sequencing in prospective longitudinal cohorts from around the world, novel therapeutic targets regulating lipid and lipoprotein metabolism, such as apoprotein C3, angiopoietin-like proteins 3 and 4, and lipoprotein(a), have been identified. These targets may provide additional avenues to prevent and treat atherosclerotic disease. We therefore review these novel molecular targets by addressing available Mendelian and observational data, therapeutic agents in development, and early outcomes results.
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Affiliation(s)
- Vasanth Sathiyakumar
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Karan Kapoor
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Steven R Jones
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland
| | - Seth S Martin
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Welch Center for Prevention, Epidemiology, and Clinical Research, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Peter P Toth
- Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, CGH Medical Center, Sterling, IL, USA.
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