Intracerebroventricular enzyme replacement therapy with ?-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice.

ABSTRACT: Autosomal recessive mutations in the galactosidase ?1 (GLB1) gene cause lysosomal ?-gal deficiency, resulting in accumulation of galactose-containing substrates and onset of the progressive and fatal neurodegenerative lysosomal storage disease, GM1 gangliosidosis. Here, an enzyme replacement therapy (ERT) approach in fibroblasts from GM1 gangliosidosis patients with recombinant human ?-gal (rh?-gal) produced in Chinese hamster ovary cells enabled direct and precise rh?-gal delivery to acidified lysosomes. A single, low dose (3 nm) of rh?-gal was sufficient for normalizing ?-gal activity and mediating substrate clearance for several weeks. We found that rh?-gal uptake by the fibroblasts is dose-dependent and saturable and can be competitively inhibited by mannose 6-phosphate, suggesting cation-independent, mannose 6-phosphate receptor-mediated endocytosis from the cell surface. A single intracerebroventricularly (ICV) administered dose of rh?-gal (100 ?g) resulted in broad bilateral biodistribution of rh?-gal to critical regions of pathology in a mouse model of GM1 gangliosidosis. Weekly ICV dosing of rh?-gal for 8 weeks substantially reduced brain levels of ganglioside and oligosaccharide substrates and reversed well-established secondary neuropathology. Of note, unlike with the ERT approach, chronic lentivirus-mediated GLB1 overexpression in the GM1 gangliosidosis patient fibroblasts caused accumulation of a prelysosomal pool of ?-gal, resulting in activation of the unfolded protein response and endoplasmic reticulum stress. This outcome was unsurprising in light of our in vitro biophysical findings for rh?-gal, which include pH-dependent and concentration-dependent stability and dynamic self-association. Collectively, our results highlight that ICV-ERT is an effective therapeutic intervention for managing GM1 gangliosidosis potentially more safely than with gene therapy approaches.

SUBMITTER: Chen JC 

PROVIDER: S-EPMC7521651 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature