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

Allele-specific antisense oligonucleotides targeting SNPs in linkage with CAG expansion can reduce mutant ATXN3 expression by up to 90% in SCA3 models.

• Why it matters: Current treatments for SCA3 lack specificity for the mutant allele, risking interference with protective wild-type protein functions. Developing allele-specific therapies could improve treatment precision and safety for patients.
• What they did: Researchers performed nanopore sequencing on 79 SCA3 patients, identified nearly 200 linked polymorphisms, and tested 17 candidate ASOs targeting SNPs across haplotype blocks, with seven achieving over 65% allele-preferential reduction.
• The result: A single ASO application in patient-derived neurons achieved up to 90% reduction of mutant ATXN3 without toxicity or widespread transcriptional effects, demonstrating the potential of haplotype-informed allele-specific silencing for SCA3 therapy.