AAV-mediated gene therapy of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber disease
Résumé
Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME)
are autosomal recessive disorders caused by mutations in the ASAH1 gene, which codes
for acid ceramidase (ACDase), a lysosomal enzyme that catalyses the bioactive lipid ceramide
into sphingosine and fatty acid. These ASAH1-related disorders present with a spectrum of
clinical manifestations and lead to death in most cases during early infancy (FD) or at teenage
(SMA-PME). To date, there is no curative treatment for patients and therefore a clear unmet
medical need. In the present study, we evaluated a gene therapy approach in a mouse model of
acid ceramidase deficiency. We report that intravenous administration of a recombinant AAV9
vector expressing human ACDase in diseased Asah1P361R/P361R mice prolonged survival of all
animals until the end of a 6-month study, restored body growth and motor activity, and
abolished inflammation in peripheral tissues and the central nervous system. Our findings
provide proof-of-concept that systemic AAV-mediated ASAH1 gene replacement can rescue
the severe phenotype of a mouse model of acid ceramidase deficiency, paving the way for
clinical translation in patients.