Study

An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons

Study ID Alternative Stable ID Type
EGAS00001006289 Other

Study Description

Huntington's disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using a GLP approved HTT assay. HD patients’ fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC50 consistently below 10nm without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Amongst, a 115bp frameshift-inducing exon in the HTT transcript in Branaplam treated cells from Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients’ fibroblasts and cortical neurons. These findings highlight the ... (Show More)

Study Datasets 2 datasets.

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Dataset ID Description Technology Samples
EGAD00001008807
n=4 Ctrl and n=4 HD fibroblasts lines were treated with DMSO or 10nM Branaplam for 72h and RNA-seq was performed.
Illumina NovaSeq 6000 16
EGAD00001008808
n=3 Ctrl and n=3 HD iPSC lines differentiated into cortical neurons were treated with DMSO or 10nM Branaplam for 72h and RNA-seq was performed.
Illumina NovaSeq 6000 12

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