Antisense oligonucleotides for the treatment of spinocerebellar ataxia type 2

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DESCRIPTION (provided by applicant): Neurodegenerative diseases represent an ever-increasing societal and economic burden with WHO estimates indicating that they will replace cancer as the 2nd leading cause of death by 2040. In neurodegenerative disease research, a wealth of pathways has been uncovered, but their direct and primary relevance to the respective human disease has been difficult to prove and targeting of pathways has remained difficult. The proposed work will identify a treatment for spinocerebellar ataxia type 2 (SCA2), a hereditary neurodegenerative disease affecting cerebellar Purkinje neurons (PNs) and other neurons in the cerebellum, brainstem and cerebrum. The cause of SCA2 is a gain-of-function CAG expansion in the ATXN2 gene resulting in an expanded polyglutamine (polyQ) in ataxin-2. Our objective is identification of antisense oligonucleotides (ASOs) that lower ATXN2 expression. Our rationale is based on observations in model organisms and humans indicating that higher dosages of the mutant allele/protein worsen disease severity and that down-regulation of mutant polyQ protein expression in rodents reverses clinical manifestations even after mice have become symptomatic. Additionally, complete knock-out of ATXN2 in mice does not cause neurodegeneration or premature death. Merit for this study is supported by positive results in clinical trials for multiple ASOs, and ongoing clinical trials to test ASOs for the treatment of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The feasibility is based on established resources including lead ASOs identified in vitro and a well-characterized human-BAC transgenic mouse model with late onset progressive motor phenotypes. Three specific aims are proposed: 1) Identification of the 4 most effective ASOs for lowering ATXN2 expression, from 15 lead ASOs that we have already identified in a preliminary ASO screen, 2) testing the ASO leads for amelioration of a biochemical endophenotype that includes indication of maintained glial health, and 3) testing the two most effective ASOs for ameliorating a motor phenotype in an SCA2 mouse BAC model. The proposed work will break new ground for treatment of neurodegenerative diseases by demonstrating feasibility of targeting dominant-acting mutated polyQ genes with antisense oligonucleotides.