Mutant huntingtin (mHTT) pre-messenger RNA at single nucleotide polymorphism 3 (SNP3) locus (mHTT pre-mRNA SNP3)

The mutant huntingtin (mHTT) pre-messenger RNA at the single nucleotide polymorphism 3 (SNP3) locus, specifically rs362331, is a therapeutic target for the treatment of Huntington's disease (HD) [Wave Life Sciences, 2024]. HD is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, which leads to the production of toxic mHTT protein [NIH, 2023]. Because wild-type huntingtin (wtHTT) is essential for neuronal survival and function, non-selective silencing of both alleles may be detrimental [Tabrizi et al., 2022]. SNP3 is a genetic marker found in linkage disequilibrium with the CAG expansion in approximately 40% of HD patients, allowing for a precision medicine approach [Datta et al., 2023]. Antisense oligonucleotides (ASOs) like WVE-003 are designed to bind selectively to the SNP3 sequence on the mutant transcript, triggering its degradation via RNase H while sparing the wtHTT transcript [Wave Life Sciences, 2024]. This allele-selective strategy aims to reduce the burden of toxic mHTT while maintaining the beneficial levels of the wild-type protein, potentially slowing disease progression [Datta et al., 2023].

Other names

rs362331HTT SNP3Huntingtin SNP3Mutant HTT pre-mRNA rs362331

Allele-selective RNase H-mediated degradation of pre-mRNA