RNA splicing modulator for Huntington’s disease treatment induces peripheral neuropathy
Year: 2025
Type: article
Abstract: 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.
Source: iScience
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,240
Funders: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius-Stiftung, Bayerisches Staatsministerium für Bildung und Kultus, Wissenschaft und Kunst, Bayerisches Staatsministerium für Wissenschaft, Forschung und Kunst, Forschungsstiftung Medizin am Universitätsklinikum Erlangen, Universitätsklinikum Erlangen
Awards: G2693943190, TreatHSP - Translationale Forschung für Hereditäre Spastische Spinalparalysen: Mobile Ganganalyse zur Klassifizierung von HSP-spezifischen Phänotypen sowie Untersuchung der Dopaminergen Degeneration bei SPG11/15-Mutationen, G2730047965, G4221214361, G5188208403, KFO 5024: ImmunCheckpoints der Kommunikation zwischen Darm und Gehirn bei entzündlichen und neurodegenerativen Erkrankungen (GB.com), GRK 2162: Entwicklung und Vulnerabilität des Zentralnervensystems, G568328559, G6818401677, iIMMUNE_ACS - Förderung von Advanced Clinician Scientists im Bereich Immunmedizin, TreatHSP.net - Translationale Forschung zur hereditären spastischen Paraplegie - Teilprojekt 2, Teilprojekt 7, G7661992826, G8808778905
OpenAlex ID: W4409255920