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Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back
Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenar...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768510/ https://www.ncbi.nlm.nih.gov/pubmed/33260623 http://dx.doi.org/10.3390/jpm10040258 |
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author | Buscara, Laurine Gross, David-Alexandre Daniele, Nathalie |
author_facet | Buscara, Laurine Gross, David-Alexandre Daniele, Nathalie |
author_sort | Buscara, Laurine |
collection | PubMed |
description | Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these “à-la-carte” therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed. |
format | Online Article Text |
id | pubmed-7768510 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77685102020-12-29 Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back Buscara, Laurine Gross, David-Alexandre Daniele, Nathalie J Pers Med Review Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these “à-la-carte” therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed. MDPI 2020-11-28 /pmc/articles/PMC7768510/ /pubmed/33260623 http://dx.doi.org/10.3390/jpm10040258 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Buscara, Laurine Gross, David-Alexandre Daniele, Nathalie Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back |
title | Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back |
title_full | Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back |
title_fullStr | Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back |
title_full_unstemmed | Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back |
title_short | Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back |
title_sort | of raav and men: from genetic neuromuscular disorder efficacy and toxicity preclinical studies to clinical trials and back |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768510/ https://www.ncbi.nlm.nih.gov/pubmed/33260623 http://dx.doi.org/10.3390/jpm10040258 |
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