1. Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.
- Author
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Liu L, Malagu K, Haughan AF, Khetarpal V, Stott AJ, Esmieu W, Vater HD, Webster SJ, Van de Poël AJ, Clissold C, Cosgrove B, Sutton B, Spencer JA, Breccia P, Gancia E, Bonomo S, Ladduwahetty T, Lazari O, Patel H, Atton HC, Clifton S, Mota DM, Magnani D, O'Neill A, Stebbeds M, Macabuag N, Todd D, Herva ME, Mitchell P, Visser M, Compte Sancerni S, Grand Moursel L, da Silva M, Kritikou E, Heikkinen TT, Bolkvadze T, Fodale V, Spadafora D, Daldin M, Bresciani A, Mangette JE, Doherty EM, Lee MR, Herbst T, Monteagudo E, Macdonald D, Plotnikov NV, Chambers M, McAllister G, Muňoz-Sanjuan I, and Dominguez C
- Abstract
Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin ( HTT ) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT -splicing modulator 27 . This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT -splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.
- Published
- 2023
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