Single-nucleotide polymorphism-directed design of allele-specific antisense oligonucleotides for spinocerebellar ataxia type 3.

Researchers used SNP genotyping from 79 SCA3 patients to design 17 candidate ASOs, 7 of which reduced mutant ATXN3 expression by more than 65% and preferentially targeted the mutant allele. Nearly 200 polymorphisms were grouped into three haplotype blocks; modeling suggested that two SNPs from different blocks could cover most European SCA3 patients. A single ASO reduced mutant ATXN3 by up to 90% in AX1 and AX2 iPSC-derived cortical neurons.