Gene therapies for spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is an adult onset, autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in ataxin-1, which encodes the ataxin-1 protein. SCA1 is one of nine polyQ-expansion gain-of-function diseases which includes Huntington's disease, spinal-bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy and other ataxias. Clinical symptoms of SCA1 include ataxia, dysarthria, ophthalmoparesis, muscle wasting, and extrapyramidal and bulbar dysfunction. Cerebellar Purkinje cells (PCs), neurons in the inferior olive and nuclei of the brainstem are affected. No disease-modifying therapy exists for SCA1. The goals of my thesis were to assess the safety and efficacy of AAV-delivered artificial miRNAs targeting ataxin-1 to alleviate neuropathological and behavioral phenotypes in the knock-in and transgenic SCA1 mouse models.

In the knock-in SCA1 mouse model AAVs expressing an artificial miRNA (miSCA1) targeting sequences conserved in mouse and human ataxin-1 were injected directly to the deep cerebellar nuclei. This achieved long term silencing of ataxin-1 mRNA and significantly improved rotarod performance, gait deficiencies, and neuropathology of the cerebellum.

In the transgenic SCA1 mouse model the same method of delivery was executed with an artificial microRNA (miR) (miS1) designed to optimize potency, efficacy and safety to suppress Atxn1 expression. Additionally the therapeutic potential of continuous overexpression of ataxin-1-like was examined. Delivery of either ataxin-1-like or miS1 viral vectors to SCA1 mouse cerebellum resulted in widespread cerebellar Purkinje cell transduction. There was significant improvement to rotarod performance, gait deficiencies, coordination and balance, as well as the neuropathology of cerebellar Purkinje cells. In summary, these data indicate the utility of these approaches as possible therapies for SCA1 patients.