Wild-type huntingtin messenger RNA (HTT mRNA)

Wild-type huntingtin (HTT) messenger RNA is the transcript produced from the non-mutated HTT gene, serving as the template for the synthesis of the huntingtin protein, which is essential for embryonic development and neuronal survival (Saudou & Humbert, 2016, Neuron). This protein is ubiquitously expressed and involved in critical cellular processes such as axonal transport, vesicle trafficking, and autophagy regulation (UniProt, P42858). In Huntington's disease (HD), a dominant neurodegenerative disorder, the presence of a mutant allele leads to toxic protein aggregation; however, the wild-type HTT protein provides neuroprotective effects that may counteract this toxicity (Leavitt et al., 2020, J. Huntingtons Dis.). Therapeutic strategies such as antisense oligonucleotides (ASOs) like Tominersen and RNA interference (RNAi) agents often target HTT mRNA to reduce protein levels (Tabrizi et al., 2019, NEJM). A major challenge in HD therapy is the potential for collateral damage when non-selective silencing reduces wild-type HTT mRNA alongside the mutant form, potentially leading to adverse effects due to loss of essential functions (Reilmann et al., 2021, Lancet Neurology). Consequently, newer allele-selective approaches, such as WVE-003, aim to specifically degrade mutant mRNA while sparing the wild-type transcript to preserve its physiological roles (Wave Life Sciences, 2024).

Other names

Huntingtin mRNAHTT transcriptIT15 mRNAWild-type HTT mRNAHD mRNA

Antisense oligonucleotide-mediated RNase H degradation, RNA interference (RNAi)-mediated cleavage, or small molecule-induced splicing modulation to reduce protein translation.