Huntingtin pre-mRNA splicing machinery (HTT pre-mRNA splicing)

The Huntingtin (HTT) pre-mRNA splicing machinery is a therapeutic target focused on reducing the levels of the toxic huntingtin protein in patients with Huntington's disease (HD). This approach utilizes small molecule splicing modulators that bind to the interface of the HTT pre-mRNA and the U1 small nuclear ribonucleoprotein (snRNP) within the spliceosome (Bhattacharyya et al., 2021, Nature Communications). By stabilizing this interaction, the drugs promote the inclusion of a cryptic exon (pseudoexon) that is normally skipped during RNA processing. The inclusion of this pseudoexon introduces a premature termination codon, which marks the mRNA for degradation via the nonsense-mediated decay (NMD) pathway, effectively lowering the translation of huntingtin protein (PTC Therapeutics, 2023). This strategy offers a systemic, orally bioavailable alternative to gene-silencing therapies like antisense oligonucleotides. However, the primary challenge lies in achieving high selectivity for the HTT transcript to minimize off-target splicing events in the transcriptome, which have been linked to safety issues such as peripheral neuropathy in clinical trials (Novartis, 2022). Despite these challenges, modulating HTT splicing remains a promising avenue for disease-modifying treatment in HD by targeting the root cause of the pathology.

Other names

HTT pre-mRNAHuntingtin RNA splicingHTT cryptic exon inclusionHTT pseudoexon splicingHTT-U1 snRNP complex

Small molecule-induced pseudoexon inclusion leading to nonsense-mediated decay (NMD)