AAV5-miHTT Gene Therapy Demonstrates Sustained Huntingtin Lowering and Functional Improvement in Huntington Disease Mouse Models

摘要: Huntington disease (HD) is a fatal neurodegenerative disorder caused by an autosomal dominant CAG repeat expansion in the huntingtin (HTT) gene. The translated expanded polyglutamine HTT protein known to cause toxic gain of function. We showed previously that strong lowering prevented neuronal dysfunction HD rodents and minipigs after single intracranial injection adeno-associated viral vector serotype 5 expressing microRNA targeting human (AAV5-miHTT). To evaluate long-term efficacy, AAV5-miHTT was injected into striatum knockin Q175 mice, mice were sacrificed 12 months post-injection. dose-dependent sustained reduction with subsequent suppression mutant aggregate formation cortex. Functional proof concept shown transgenic R6/2 mice. Eight weeks treatment, significant improvement motor coordination on rotarod observed. Survival analysis treatment resulted 4-week increase median survival compared vehicle-treated combination lowering, aggregation, prevention dysfunction, alleviation HD-like symptoms, beneficial observed treated supports continued development HTT-lowering gene therapies for HD.