Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington’s Disease

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.