Intracerebroventricular enzyme replacement therapy with β-galactosidase reverses brain pathologies due to GM1 gangliosidosis in mice
| Autor: | Alexander Giaramita, Nathan Wise, Jon Vincelette, Rolando De Angelis, Brett E. Crawford, Sherry Bullens, Nicole Galicia, Melanie J. Lo, Jeremy L. Van Vleet, Sushmita M Roy, Gouri Yogalingam, Amanda R. Luu, Linley Mangini, Alessandra d'Azzo, Vishal Agrawal, Glenn Pacheco, Sylvia Fong, Jonathan H. LeBowitz, Terri Christianson, Hio Wong, Roger Lawrence, Britta Handyside, Harry J Sterling, Stuart Bunting, Chuck Hague, Joseph C Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
safety medicine.medical_specialty GM1 gangliosidosis Biochemistry enzyme replacement therapy (ERT) 03 medical and health sciences Mice Internal medicine Lysosome biophysics Lysosomal storage disease medicine Animals cation-independent mannose-6-phosphate receptor Enzyme Replacement Therapy unfolded protein response (UPR) Molecular Biology Ganglioside Gangliosidosis GM1 030102 biochemistry & molecular biology Chemistry Chinese hamster ovary cell Endoplasmic reticulum neurodegeneration toxicity Enzyme replacement therapy Cell Biology medicine.disease beta-Galactosidase gene therapy 030104 developmental biology medicine.anatomical_structure Endocrinology GLB1 lysosomal storage disease Unfolded protein response lysosome endoplasmic reticulum stress |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Autosomal recessive mutations in the galactosidase β1 (GLB1) gene cause lysosomal β-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 β-gal (rhβ-gal) produced in Chinese hamster ovary cells enabled direct and precise rhβ-gal delivery to acidified lysosomes. A single, low dose (3 nm) of rhβ-gal was sufficient for normalizing β-gal activity and mediating substrate clearance for several weeks. We found that rhβ-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 rhβ-gal (100 μg) resulted in broad bilateral biodistribution of rhβ-gal to critical regions of pathology in a mouse model of GM1 gangliosidosis. Weekly ICV dosing of rhβ-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 β-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 rhβ-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. |
| Databáze: | OpenAIRE |
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