Development of an allele-specific epigenetic silencing platform for the treatment of SCA2

Spinocerebellar ataxia type 2 (SCA2) is a rare debilitating disease of the nervous system caused by mutations in the gene Ataxin-2 (ATXN2). In healthy subjects, ATXN2 contains a 22-long repetition of three nucleotides, whereas in SCA2 patients a copy of this gene contains over 33 of such repetitions. The link between the pathogenic expansion and the clinical signs is poorly understood. However, the most accredited hypothesis indicates that the ATXN2 protein, encoded by the gene containing the pathogenic expansion, forms toxic products in the neurons, a relevant cell type of the nervous system. Unfortunately, the prognosis of SCA2 patients is very poor, and the available pharmacologic interventions are just symptomatic. In this project, we aim at developing a new gene therapy approach for SCA2 able to silence the mutated ATXN2 gene. To reach this goal, we will refine a gene therapy technology that we recently developed, termed epigenetic editing. This technology is based on the transient administration of artificial proteins able to recognize the desired gene, where they permanently edit the code that governs gene expression, namely epigenetics. If successful, this project will pave the way to the development of a safe and efficient therapeutic strategy for SCA2, portable to other diseases caused by pathogenic trinucleotide expansions.