Tay-Sachs and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the HEXA and HEXB genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase (HexA) that degrades GM2 ganglioside. This report describes a 5 year-long study using a bidirectional AAV9 vector (AAV9-Bic_HexA/HexB) encoding both HEXA and HEXB in the Tay-Sachs sheep model. Bidirectional AAV9 was delivered intravenously or through various cerebral spinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM) and lumbar delivery (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV and LIT) with treated animals survived up to 5 years of age (untreated Tay-Sachs animals die ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy including MRI, MR spectroscopy, diffusion tensor imaging as well as CSF levels of GM2 ganglioside and hexosaminidase A (HexA) activity was evident. Post-mortem assessments showed broad HexA distribution, GM2 ganglioside clearance and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in Tay-Sachs and Sandhoff disease patients.