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Poster De Conférence Année : 2022

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.
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Dates et versions

hal-04453834 , version 1 (12-02-2024)

Identifiants

  • HAL Id : hal-04453834 , version 1

Citer

Jérôme Denard, Martina Marinello, Virginie Latournerie, Delphine Bonnin, Marion Derome, et al.. AAV-mediated gene therapy of acid ceramidase deficiency. Myology 2022, Sep 2022, Nice, France. ⟨hal-04453834⟩
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