CENTRAL TIME ZONE

Explore a past NAF research grant awardee’s funded study, gaining scientific insights about their Ataxia research.

Dr. Collin Anderson will present the research, “Gene therapy in the shaker rat model of Christianson syndrome.”

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Research Lay Summary: Our work revolves around the generation of a novel gene therapy to treat a form of degenerative cerebellar ataxia. We have spent several years characterizing the cellular, molecular, and motor abnormalities of the shaker rat, a naturally occurring genetic rodent model of Purkinje cell degeneration, cerebellar tremor, and ataxia. In studying the shaker rat, we identified the causative mutation: shaker rats lack a functional NHE6 ion channel, which functions by removing hydrogen ions from Purkinje cells and replaces them with sodium ions. In the absence of this channel, cells become overly acidic and eventually die, leading to severe ataxia and tremor. Mutations of the gene encoding this ion channel lead to Christianson Syndrome in humans, which includes a severe, debilitating, progressive ataxia. We are working to characterize and optimize the effects of a new therapeutic strategy in this model: we have designed an adeno-associated virus that expresses the unmutated gene in Purkinje cells, generating a functional NHE6 protein. Adeno-associated viruses are a particularly attractive method of gene therapy in humans, as they don’t cause disease in humans, don’t replicate, and have long-lasting effects. Additionally, we have designed this virus using the newest engineered variant, enabling not only high efficacy with low dose, but ability to cross the blood-brain barrier. Therefore, success in our work will lead to easier translation than that in most therapeutic strategies. We have already generated very strong preliminary data showing that, at least over a moderate term, this viral therapeutic can prevent the generation of phenotype, but we still need to determine whether whether we are preventing the phenotype or simply delaying it. We need to perform experiments to optimize the therapy, and, further, while AAVs are known to be safely tolerated, we need to evalute the safety profile of the gene expression. Not only will this work develop a translatable therapy for ataxia associated with Christianson Syndrome, but it will prove the concept of using gene therapies to restore missing protein expression in order to treat a degenerative ataxia, which has major implications for the way we treat ataxias.