AAV-mediated gene therapy corrects the severe phenotype of acid ceramidase deficient mice - Archive ouverte HAL Accéder directement au contenu
Poster De Conférence Année : 2023

AAV-mediated gene therapy corrects the severe phenotype of acid ceramidase deficient mice

Résumé

Acid ceramidase deficiency is a group of autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene that codes for acid ceramidase (ACDase). This enzyme cleaves ceramide into sphingosine and fatty acid. These ASAH1-related disorders present with a spectrum of clinical manifestations during early (Farber disease, FD) or late infancy/ teenage (spinal muscular atrophy with progressive myoclonic epilepsy, SMA-PME). To date, there is no curative treatment for patients and therefore a clear unmet medical need. We recently established proof-of-concept studies that intravenous administration of a recombinant AAV9 vector expressing human ACDase in Asah1P361R/P361R mice at pre- and post-symptomatic stages of the disease is able to prolong the lifespan and correct the phenotype. Here, we performed a dose escalation study in Asah1P361R/P361R mice to determine the minimum effective dose (MED) of this vector. Three doses of AAV9-ASAH1 were administrated intravenously in mutant mice at a late stage of the disease and the effect was analyzed at the clinical, molecular and histological level for a 6-month period. We found that the low dose was suboptimal, whereas most pathological parameters were corrected at mid dose. However, detailed histological analysis of treated mice 6 months post-injection revealed that administration of the vector at the high dose was able to avoid the presence of inflammatory infiltrates in some tissues, including the central nervous system. These results pave the way for preclinical development and clinical translation of this treatment in patients with Farber and SMA-PME diseases.
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Dates et versions

hal-04453843 , version 1 (12-02-2024)

Identifiants

  • HAL Id : hal-04453843 , version 1

Citer

Jérôme Denard, Martina Marinello, Virginie Latournerie, Delphine Bonnin, Marion Derome, et al.. AAV-mediated gene therapy corrects the severe phenotype of acid ceramidase deficient mice. ASGCT 2023, May 2023, Los Ageles, United States. ⟨hal-04453843⟩
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