Wild-type huntingtin mRNA (HTT mRNA)

Wild-type huntingtin (HTT) mRNA is the transcript produced from the HTT gene that contains a non-pathogenic number of CAG repeats, typically defined as 35 or fewer (Source: UniProt P42858). This mRNA is translated into the huntingtin protein, a large scaffold protein that is essential for embryonic development and the survival of neurons in the adult brain (Source: PubMed 29070657). The protein product of this mRNA facilitates the transport of vesicles and organelles along the cytoskeleton and is crucial for the axonal transport of brain-derived neurotrophic factor (BDNF) (Source: PubMed 15247477). In the context of Huntington's disease (HD) therapeutics, wild-type HTT mRNA is a significant target for non-allele-specific gene-silencing agents, such as the antisense oligonucleotide tominersen, which reduces both mutant and wild-type HTT levels (Source: NEJM 380:2307-2318). While reducing the toxic mutant protein is the primary therapeutic goal, the depletion of wild-type HTT mRNA presents a major safety concern, as the loss of wild-type HTT function may impair neuronal health and contribute to the progression of neurodegeneration (Source: PubMed 33826815). Consequently, current drug development efforts are increasingly focused on preserving wild-type HTT levels through allele-specific targeting or carefully titrated splicing modulation using small molecules like PTC518 (Source: PTC Therapeutics). Monitoring total HTT levels in the cerebrospinal fluid serves as a key biomarker for assessing the impact of these therapies on the wild-type transcript (Source: PubMed 31067372).

Other names

HTT transcriptHuntingtin messenger RNAWild-type HTT transcriptNormal CAG length huntingtin mRNA

Antisense oligonucleotide-mediated RNase H degradation and small molecule-induced pseudo-exon inclusion leading to mRNA degradation.