Mutant huntingtin messenger RNA (mHTT mRNA) (SNP rs7685686) (mHTT mRNA (rs7685686))

Mutant huntingtin messenger RNA (mRNA) containing the single nucleotide polymorphism (SNP) rs7685686 is a specific therapeutic target for the treatment of Huntington's disease (HD). HD is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, which produces a toxic mutant huntingtin (mHTT) protein (MacDonald et al., 1993). Because the wild-type huntingtin (wtHTT) protein is essential for neuronal survival and function, therapeutic approaches aim to selectively reduce the mutant form while preserving the wild-type form (Zuccato et al., 2010). The rs7685686 SNP is a genetic variation that is frequently linked to the mutant allele in a significant portion of the HD population, serving as a molecular handle for allele-specific silencing (Pfister et al., 2009). Investigational drugs like the antisense oligonucleotide WVE-120101 are designed to bind specifically to the mRNA sequence containing this SNP, recruiting RNase H to degrade the mutant transcript (Wave Life Sciences, 2021). This precision medicine approach seeks to prevent the translation of toxic mHTT protein, thereby slowing or halting disease progression (Skotte et al., 2014). Clinical monitoring of this target involves genotyping patients for the presence of the rs7685686 SNP and measuring mHTT protein levels in the cerebrospinal fluid as a pharmacodynamic biomarker.

Other names

HTT mRNAHuntingtin mRNAMutant HTT transcriptrs7685686-containing HTT mRNA

Allele-selective mRNA degradation via RNase H-mediated cleavage