RNA splicing modulator for Huntington's disease treatment induces peripheral neuropathy.

RNA splicing modulators, a new class of small molecules with the potential to modify the protein expression levels, have quickly been translated into clinical trials. These compounds hold promise for treating neurodegenerative disorders, including branaplam for lowering huntingtin levels in Huntington's disease. However, the VIBRANT-HD trial was terminated due to the emergence of peripheral neuropathy. Here, we describe the complex mechanism whereby branaplam activates p53, induces nucleolar stress in human induced pluripotent stem cell (iPSC)-derived motor neurons (iPSC-MN), and thereby enhanced expression of the neurotoxic p53-target gene BBC3. On the cellular level, branaplam disrupts neurite integrity, reflected by elevated neurofilament light chain levels. These findings illustrate the complex pharmacology of RNA splicing modulators with a small therapeutic window between lowering huntingtin levels and the clinically relevant off-target effect of neuropathy. Comprehensive toxicological screening in human stem cell models can complement pre-clinical testing before advancing RNA-targeting drugs to clinical trials.