AAV gene therapy in a sheep model of Tay-Sachs disease (original) (raw)

Human gene therapy, 2017

Abstract

Tay-Sachs disease (TSD) is a fatal neurodegenerative disorder caused by a deficiency of the enzyme hexosaminidase A (HexA). Tay-Sachs disease also occurs in sheep, the only experimental model of TSD that has clinical signs of disease. The natural history of sheep TSD was characterized using serial neurological evaluations, 7 tesla MRI, echocardiograms, electrodiagnostics and cerebrospinal fluid (CSF) biomarkers. Intracranial gene therapy was also tested using AAVrh8 monocistronic vectors encoding the α subunit of Hex (TSD α) or a mixture of two vectors encoding both the α and β subunits separately (TSD α+β) injected at high (1.3 x1013vg) or low (4.2x1012vg) dose. Delay of symptom onset and/or reduction of acquired symptoms were noted in all AAV treated sheep. Post-mortem evaluation showed superior HexA and vector genome distribution in the brain of TSD α+β sheep compared to TSD α sheep, but spinal cord distribution was low in all groups. Isozyme analysis showed superior HexA formati...

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