AAV-mediated gene therapy of acid ceramidase deficiency
Résumé
Acid ceramidase deficiency is an orphan disorder caused by mutations in the ASAH1 gene
presenting with a spectrum of clinical manifestations that leads to death in most cases during
early infancy (Farber disease, FD) or at teenage (spinal muscular atrophy with progressive
myoclonic epilepsy, SMA-PME). Acid ceramidase (ACDase) is a lysosomal enzyme that
catalyses bioactive ceramides into sphingosine and fatty acid. 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. In addition, we performed a dose-finding study and
quantified blood biomarkers of the disease before and after treatment. Our findings provide
proof-of-concept that systemic AAV-mediated ASAH1 gene replacement can correct the severe
phenotype of a mouse model of acid ceramidase deficiency, and pave the way for clinical
translation in patients.