Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back.
Laurine BuscaraDavid-Alexandre GrossNathalie DanielePublished in: Journal of personalized medicine (2020)
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.
Keyphrases
- gene therapy
- duchenne muscular dystrophy
- clinical trial
- skeletal muscle
- genome wide
- muscular dystrophy
- endothelial cells
- copy number
- genome wide identification
- insulin resistance
- climate change
- oxidative stress
- phase ii
- dna methylation
- induced pluripotent stem cells
- late onset
- cancer therapy
- adipose tissue
- depressive symptoms
- double blind
- stem cells
- phase iii
- randomized controlled trial
- genome wide analysis
- open label
- metabolic syndrome
- type diabetes
- middle aged
- study protocol
- physical activity
- atrial fibrillation
- case control
- early onset