Intrathecal delivery of AAVrh10-mHexa combined with anti-inflammatory treatment reduces neuropathological markers and extends the lifespan of mice with early-onset Tay-Sachs disease.

Tay-Sachs disease is a lysosomal storage disorder caused by mutations in the HEXA gene, which encodes the α-subunit of β-hexosaminidase A-an enzyme that breaks down GM2 ganglioside. Recently, a mouse model of Tay-Sachs, the DKO, with deficiencies in both Hexa and Neu3 genes, showed severe neurological symptoms and neuroinflammation, surviving up to 20 weeks. In this study, we evaluated the therapeutic potential of intrathecal AAVrh10-mediated delivery of mouse Hexa, in combination with istradefylline treatment, in DKO mice. Using molecular, immunohistochemical, and behavioral methods, we found that the mice's lifespan increased to 30 weeks after receiving AAV alone or with istradefylline. Molecular analyses revealed increased Hexa activity, accompanied by reduced levels of the lysosomal marker Lamp-1 and pro-inflammatory cytokines, such as CCL2 and CCL3, in the cortex, cerebellum, and various organs, including the kidney, liver, and spleen. Immunohistochemistry revealed clearance of GM2 accumulation, fewer lysosomes, decreased active astrocytes, and improvements in neurons and oligodendrocytes in the brains of DKO mice. Correspondingly, their motor activity also improved. These results suggest that AAVrh10-based intrathecal delivery combined with istradefylline provides a promising therapeutic strategy for treating Tay-Sachs disease.