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

Neurobiol Dis. 2022 Mar:164:105628. doi: 10.1016/j.nbd.2022.105628. Epub 2022 Jan 13.

Abstract

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.

Keywords: Autophagy; CLN10 disease; Cathepsin D; Enzyme replacement therapy; Gene therapy; Lysosome; Neural stem cells; Neuronal ceroid lipofuscinosis; Retinal degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Cathepsin D / genetics*
  • Cathepsin D / metabolism
  • Disease Models, Animal
  • Genetic Therapy*
  • Lysosomes / physiology*
  • Mice
  • Mice, Knockout
  • Retinal Degeneration / genetics
  • Retinal Degeneration / therapy*

Substances

  • Cathepsin D