Huntingtin messenger RNA (wild-type) (HTT mRNA)

Wild-type Huntingtin (HTT) messenger RNA is the transcript produced from the non-mutated HTT gene, encoding a large scaffolding protein essential for various cellular processes, including vesicular transport, endocytosis, and transcriptional regulation (Saudou & Humbert, 2016, Neuron). In Huntington's Disease (HD), a dominant neurodegenerative disorder, the presence of a mutant allele leads to the production of toxic mutant HTT protein; however, the wild-type protein remains critical for neuronal survival and the transport of brain-derived neurotrophic factor (BDNF) (Zuccato et al., 2001, Science). Therapeutic interventions such as antisense oligonucleotides (ASOs) and RNA interference (RNAi) are designed to target HTT mRNA to lower protein levels. While non-selective agents like Tominersen reduce both mutant and wild-type HTT mRNA, there is a significant safety concern that depleting the wild-type transcript may impair normal neuronal function (Tabrizi et al., 2022, NEJM). Consequently, modern drug development often focuses on allele-selective targeting to degrade mutant HTT mRNA while sparing the wild-type transcript to maintain its neuroprotective functions.

Other names

Wild-type HTT transcriptIT15 mRNAHTT mRNAHuntingtin mRNA

Antisense oligonucleotides (ASOs) and small molecule splicing modulators target the mRNA to induce degradation via RNase H or alter splicing patterns to reduce protein translation (Tabrizi et al., 2019, NEJM).