Mutant huntingtin messenger RNA (carrying target SNP) (mHTT mRNA)

Mutant huntingtin messenger RNA (mHTT mRNA) carrying a target single nucleotide polymorphism (SNP) is a specialized therapeutic target for the treatment of Huntington's disease (HD). HD is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, which results in the production of a toxic mutant protein (UniProt P42858). Because the wild-type huntingtin protein is essential for neuronal survival and health, therapeutic strategies aim to selectively reduce the mutant form while sparing the healthy version (Nature Medicine, 2019). By targeting specific SNPs that are in linkage disequilibrium with the CAG expansion, antisense oligonucleotides (ASOs) can achieve allele-specific silencing. This approach utilizes the genetic variation between the two alleles to guide the degradation of only the disease-causing transcript. Clinical candidates like WVE-003 are designed to bind to these SNPs, triggering RNase H-mediated cleavage of the mutant mRNA (Wave Life Sciences, 2024). Successful targeting results in lowered levels of toxic mHTT protein in the brain, potentially slowing or halting disease progression while maintaining the neuroprotective functions of the wild-type protein (PubMed: 31061532).

Other names

Mutant HTT mRNASNP-targeted huntingtin mRNAAllele-specific huntingtin mRNAmHTT transcriptHuntingtin messenger RNA

Allele-specific degradation of mutant mRNA via RNase H-mediated cleavage or RNA interference, guided by complementary oligonucleotide binding to a specific single nucleotide polymorphism (SNP) unique to the mutant allele.