Abstract
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an autosomal recessive disorder caused by mutations in the <i>ASAH1</i> gene, which codes for acid ceramidase (ACD), a lysosomal enzyme that catalyses the bioactive lipid ceramide into sphingosine and fatty acid. The disease is progressive, starting during childhood with muscle weakness and/or myoclonic seizures, and leads to death in most cases at teenage. To date, there is no curative treatment 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 ACD in diseased <i>Asah1</i><sup>P361R/P361R</sup> 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 <i>ASAH1</i> gene replacement can correct the severe phenotype of a mouse model of acid ceramidase deficiency, paving the way for clinical translation in patients.
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