ArticleiScience2025
RNA splicing modulator for Huntington's disease treatment induces peripheral neuropathy.
Article in iScience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Oral splicing modulator branaplam in Huntington's disease: a phase 2 randomized controlled trial.Nature medicine · 2026Trial
- Fluid and Imaging Biomarkers in Huntington's Disease.Current neurology and neuroscience reports · 2026Review
- Impact of mRNA and protein isoforms in lipoprotein metabolism and how to modulate them.Current opinion in lipidology · 2026Review
- Systematic characterization of existing and novel inducible transgenic systems in human pluripotent stem cells after prolonged differentiation.bioRxiv : the preprint server for biology · 2025Article
- Evidence that minocycline treatment confounds the interpretation of neurofilament as a biomarker.Brain communications · 2025Article
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.