Spinal muscular atrophy (SMA) is a rare neuromuscular disorder. It is characterized by degeneration of the nerve cells in the anterior horn of the spinal cord and the lower part of the brain (brainstem) which control muscle movement: the peripheral motor neurons. The muscle fibers cannot survive without being innervated and the decrease in the number of muscle fibers causes weakness and muscle loss (atrophy).
There are several forms of spinal muscular atrophy which are divided into 3 types depending on the muscles that are affected: proximal spinal muscular atrophy, distal spinal muscular amyotrophy and spinal-bulbar muscular amyotrophy. .The specificity of proximal spinal muscular atrophy is that it first affects the limb muscles closest to the trunk (proximal muscles) such as the shoulder and hip muscles.
The most common form of proximal spinal muscular atrophy is related to abnormalities detected in the SMN1 (SMA) gene, located on chromosome 5. Several subtypes have been defined (from I to IV) according to the age of onset and the severity of muscle weakness.
Type I, the acute form of SMA, is the most severe form of the disease. It manifests at birth or before six months of age causing severe hypotonia and motor dysfunction of all four limbs and trunk. Death usually occurs in the first two years of life due to respiratory failure.
There is currently no cure for these conditions which affect one in 6,000 newborns.
Genethon, together with the Institut de Myologie (Paris), has developed gene therapy that can replace the absence of this SMN protein in patients with spinal muscular atrophy, and in particular, infants with type I SMA.
Proof of concept of the efficacy of gene therapy, based on the administration of an Adeno-Associated Virus (AAV) vector carrying the human SMN1 sequence, was demonstrated by Dr Martine Barkats’ team (Institut de Myologie – INSERM UMR 974, Paris) using a mouse model (Dominguez et al., Journal Hum Mol Genet 2010).
This work led to the development of a treatment by AveXis that could be granted marketing authorization in 2019.