Intravitreal gene therapy restores the autophagy-lysosomal pathway and attenuates retinal degeneration in cathepsin D-deficient mice

• Published in: Neurobiology of disease 2022-03, Vol.164, p.105628-105628, Article 105628
• Main Authors: Liu, Junling, Bassal, Mahmoud, Schlichting, Stefanie, Braren, Ingke, Di Spiezio, Alessandro, Saftig, Paul, Bartsch, Udo
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Autophagy - physiology; Cathepsin D; Cathepsin D - genetics; Cathepsin D - metabolism; CLN10 disease; Disease Models, Animal; Enzyme replacement therapy; Gene therapy; Genetic Therapy; Lysosome; Lysosomes - physiology; Mice; Mice, Knockout; Neural stem cells; Neuronal ceroid lipofuscinosis; Retinal degeneration; Retinal Degeneration - genetics; Retinal Degeneration - therapy
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2022.105628

Loss of vision due to progressive retinal degeneration is a hallmark of neuronal ceroid lipofuscinoses (NCL), a group of fatal neurodegenerative lysosomal storage diseases. Enzyme substitution therapies represent promising treatment options for NCLs caused by dysfunctions of soluble lysosomal enzymes. Here, we compared the efficacy of a cell-based enzyme substitution strategy and a gene therapy approach to attenuate the retinal pathology in cathepsin D- (CTSD) deficient mice, an animal model of CLN10 disease. Levels of enzymatically active CTSD in mutant retinas were significantly higher after an adeno-associated virus vector-mediated CTSD transfer to retinal glial cells and retinal pigment epithelial cells than after intravitreal transplantations of a CTSD overexpressing clonal neural stem cell line. In line with this finding, the gene therapy treatment restored the disrupted autophagy-lysosomal pathway more effectively than the cell-based approach, as indicated by a complete clearance of storage, significant attenuation of lysosomal hypertrophy, and normalized levels of the autophagy marker sequestosome 1/p62 and microtubule-associated protein 1 light chain 3-II. While the cell-based treatment did not prevent the rapidly progressing loss of various retinal cell types, the gene therapy approach markedly attenuated retinal degeneration as demonstrated by a pronounced rescue of photoreceptor cells and rod bipolar cells. •A gene therapy approach restored CTSD enzymatic activity close to wild-type levels.•The treatment fully restored the disrupted autophagy-lysosomal pathway.•The therapy markedly promoted the survival of photoreceptors and rod bipolar cells.