Selective targeting of mutant huntingtin intron 1 improves rescue provided by antisense oligonucleotides in Huntington's disease mice - PubMed
3 hours ago
- #HTT1a transcript
- #Huntington's disease
- #antisense oligonucleotide
- Huntington's disease (HD) is caused by a CAG expansion in the HTT gene, leading to toxic gain of function.
- Somatic instability in mutant HTT's CAG repeat tract contributes to HD pathogenesis, including the generation of the toxic HTT1a transcript.
- Researchers developed a mutant-specific antisense oligonucleotide (MutASO) targeting HTT intron 1 to selectively reduce mutant HTT and HTT1a in HD mice.
- MutASO showed superior efficacy compared to non-allele-selective ASOs, nearly eliminating aggregate formation and protecting against transcriptional dysregulation.
- Targeting the region upstream of HTT1a's polyadenylation sites with MutASO effectively reduced HTT1a levels, suggesting its significant role in HD pathology.
- The findings highlight HTT1a's disproportionate impact on HD symptoms and suggest its reduction as a therapeutic strategy.