rAAV-mediated over-expression of acid ceramidase prevents retinopathy in a mouse model of Farber lipogranulomatosis.

Abstract

Farber disease (FD) is a rare monogenic lysosomal storage disorder caused by mutations in ASAH1 that results in a deficiency of acid ceramidase (ACDase) activity and the abnormal systemic accumulation of ceramide species, leading to multi-system organ failure involving neurological decline and retinopathy. Here we describe the effects of rAAV-mediated ASAH1 over-expression on the progression of retinopathy in a mouse model of FD (Asah1P361R/P361R) and its littermate controls (Asah1+/+ and Asah1+/P361R). Using a combination of non-invasive multimodal imaging, electrophysiology, post-mortem histology and mass spectrometry we demonstrate that ASAH1 over-expression significantly reduces central retinal thickening, ceramide accumulation, macrophage activation and limits fundus hyper-reflectivity and auto-fluorescence in FD mice, indicating rAAV-mediated over-expression of biologically active ACDase protein is able to rescue the anatomical retinal phenotype of Farber disease. Unexpectedly, ACDase over-expression in Asah1+/+ and Asah1+/P361R control eyes was observed to induce abnormal fundus hyper-reflectivity, auto-fluorescence and retinal thickening that closely resembles a FD phenotype. This study represents the first evidence of a gene therapy for Farber disease-related retinopathy. Importantly, the described gene therapy approach could be used to preserve vision in FD patients synergistically with broader enzyme replacement strategies aimed at preserving life.

• Authors: Hanmeng Zhang, Murtaza S Nagree, Haoyuan Liu, Xiaoqing Pan, Jeffrey A Medin, Daniel M Lipinski
• Journal: Gene therapy (Gene Ther) Vol. 30 Issue 3-4 Pg. 297-308 (04 2023) ISSN: 1476-5462 [Electronic] England
• PMID: 35902747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Acid Ceramidase
• Ceramides

Topics

• Mice
• Animals
• Farber Lipogranulomatosis (genetics, therapy, metabolism)
• Acid Ceramidase (genetics, metabolism)
• Ceramides (metabolism)
• Mutation
• Retinal Diseases (genetics, therapy)