Huntingtin messenger RNA (HTT mRNA)

Huntingtin messenger RNA (HTT mRNA) is the transcript of the HTT gene, which encodes a large protein involved in various cellular processes including vesicle transport, endocytosis, and transcriptional regulation (UniProt P42858). In Huntington's disease (HD), an autosomal dominant expansion of CAG repeats in the HTT gene results in a mutant mRNA that translates into a toxic protein with an elongated polyglutamine tract, leading to progressive neurodegeneration (Tabrizi et al., 2019, NEJM). Therapeutic strategies targeting HTT mRNA aim to reduce the production of this toxic protein by promoting the degradation of the transcript or modulating its splicing (Vachey and Déglon, 2018, Frontiers in Neuroscience). These approaches include non-selective antisense oligonucleotides (ASOs) like tominersen, which reduce both mutant and wild-type mRNA, and allele-selective ASOs like WVE-003 that target specific single nucleotide polymorphisms (SNPs) to spare the wild-type transcript (Wave Life Sciences, 2024). Small molecule splicing modifiers, such as PTC518, are also being developed to lower HTT levels by inducing the inclusion of a pseudo-exon that leads to mRNA degradation (PTC Therapeutics, 2024). A major challenge in this field is balancing the reduction of toxic mutant HTT with the preservation of the essential, neuroprotective functions of the wild-type HTT protein (Kwon, 2021, Nature).

Other names

Huntingtin mRNAHTT transcriptmHTT mRNAIT15 mRNA

Antisense oligonucleotide-mediated RNase H degradation, RNA interference (RNAi), and small molecule-induced splicing modulation leading to mRNA degradation.