RNA splicing modulator induces peripheral neuropathy with increased neurofilament light chain levels via p53 signaling

RNA splicing modulators are a new class of small molecules with the potential to modify the expression levels of proteins. A recent clinical trial investigating the splicing modulator branaplam for Huntingtons disease to lower huntingtin levels was terminated due to the development of peripheral neuropathy. Here, we describe how branaplam leads to this adverse effect. On a cellular level, branaplam disrupts neurite integrity reflected by elevated neurofilament light chain levels in human induced pluripotent stem cell (iPSC)-derived motor neurons (iPSC-MN). Branaplam does not target neuropathy-associated genes. However, transcription factor binding site enrichment analysis indicates p53 activation. P53 activation upon branaplam treatment in iPSC-MN is linked to increased nucleolar stress, thereby enhanced expression of the neurotoxic p53-target gene BBC3. These findings illustrate that RNA splicing modulators may have clinically relevant off-target effects, implying the necessity of comprehensive pre-screening in human models prior to executing clinical trials. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/551640v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@9b2cbdorg.highwire.dtl.DTLVardef@1964746org.highwire.dtl.DTLVardef@121612corg.highwire.dtl.DTLVardef@72c6a6_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryPredicting side effects of RNA splicing modulator branaplam leading to neurotoxicity via nucleolar stress, p53 activation, and axonal degeneration.