Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back

Abstract

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.

Novel vectors and approaches for gene therapy in liver diseases

“…Thus, special attention should be given when treating patients with preexisting hepatic conditions, which is common for IMLD patients. 142 However, it is noteworthy to indicate that clinical trials using AAV for AIP, OTC deficiency, or GSD1a have not reported major adverse events. 85 An additional very important immune-related limitation is the presence of preexisting humoral antibodies and memory T cells against the viral vectors which can completely block liver transduction.…”

“…Thus, special attention should be given when treating patients with pre-existing hepatic conditions, which is common for patients with IMLD. 142 However, it is noteworthy that clinical trials using AAV for AIP, OTC deficiency, or GSD1a have not reported major adverse events. 85 …”

Micro/mini-dystrophines et dystrophie musculaire de Duchenne : entre espoirs et défis

“…Une amélioration du transgène est également visée. Il semble que les micro-dystrophines comportant des domaines de type spectrine R16-R17 (domaines impliqués dans la liaison avec le régulateur du métabolisme cellulaire via l'oxyde nitrique synthase), pourraient avoir des avantages thérapeutiques supplémentaires [10].…”

Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function

“…The continuing development and application of multiomics methods offer particular challenges and opportunities, not least in the potential for personalized medicine. More than 500 different genes are known to be associated with neuromuscular disorders [1], and the identification of causative mutations has allowed the development of personalized therapies [1,2]. However, even if great progress has been made during the last two decades in different subgroups of neuromuscular disorders, there are still numerous challenges to resolve, such as the optimization of therapeutic knock-down strategies [3], targeting specific muscles and/or tissues of the nervous system [1], identifying genetic modifiers that can impair a therapeutic strategy [2], targeting common pathways being affected in different patient subgroups for a given disease [4,5], or understanding the impact of neuromuscular disorders on other tissues that could be affected but may be understudied.…”

“…More than 500 different genes are known to be associated with neuromuscular disorders [1], and the identification of causative mutations has allowed the development of personalized therapies [1,2]. However, even if great progress has been made during the last two decades in different subgroups of neuromuscular disorders, there are still numerous challenges to resolve, such as the optimization of therapeutic knock-down strategies [3], targeting specific muscles and/or tissues of the nervous system [1], identifying genetic modifiers that can impair a therapeutic strategy [2], targeting common pathways being affected in different patient subgroups for a given disease [4,5], or understanding the impact of neuromuscular disorders on other tissues that could be affected but may be understudied. This Special Issue, entitled "Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function", encompasses some 15 publications from colleagues working on a diverse range of neuromuscular diseases, including Duchenne muscular dystrophy [6][7][8][9], facioscapulohumeral dystrophy [3,10,11], amyotrophic lateral sclerosis [4,5,12], spinal muscular atrophy [2], Emery-Dreifuss muscular dystrophy [13], and rheumatoid arthritis [14].…”