Huntingtin pre-mRNA splicing regulatory sequences (HTT pre-mRNA)

Huntingtin (HTT) pre-mRNA splicing regulatory sequences are specific regions within the primary transcript of the HTT gene that control the assembly of the mature messenger RNA (Bhattacharyya et al., 2021). These sequences have become a focal point for therapeutic intervention in Huntington's disease (HD), a fatal neurodegenerative condition caused by an expanded CAG repeat in the HTT gene (Tabrizi et al., 2020). Small molecule splicing modulators (SMSMs) target these sequences to alter the splicing pattern, specifically by promoting the inclusion of a cryptic or 'pseudo-exon' that is normally excluded (Ratni et al., 2018). This included pseudo-exon contains a premature stop codon, which marks the mRNA for degradation via the nonsense-mediated decay (NMD) pathway (PTC Therapeutics, 2024). By reducing the stability of the HTT transcript, these drugs effectively lower the production of the toxic mutant huntingtin protein. While this approach offers a systemic, orally available alternative to intrathecal antisense oligonucleotides, it requires careful monitoring for off-target splicing of other genes (Novartis, 2022). Clinical candidates like PTC518 and branaplam have demonstrated the ability to reduce HTT levels in patients, though safety profiles regarding peripheral nerve health remain a critical consideration (ClinicalTrials.gov, NCT05358717).

Other names

HTT pre-messenger RNAHuntingtin pre-mRNAHTT cryptic exon regulatory elementsHTT pseudo-exon sequences

Small molecule-induced pseudo-exon inclusion leading to nonsense-mediated decay (NMD) of HTT mRNA