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

Florian Krach, Judith Stemick, Tom Boerstler, Alexander Weiss, Ioannis Lingos, Stephanie Reischl, Holger Meixner, Sonja Ploetz, Michaela Farrell, Ute Hehr, Zacharias Kohl, Beate Winner () and Juergen Winkler ()
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Florian Krach: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Judith Stemick: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Tom Boerstler: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Alexander Weiss: Evotec SE
Ioannis Lingos: Evotec SE
Stephanie Reischl: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Holger Meixner: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Sonja Ploetz: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Michaela Farrell: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Ute Hehr: Zentrum für Humangenetik Regensburg
Zacharias Kohl: University of Regensburg
Beate Winner: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)
Juergen Winkler: Friedrich-Alexander University of Erlangen-Nürnberg (FAU)

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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 mesoscale discovery (MSD) HTT assays. 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 10 nM without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Among these Branaplam-induced exons, there is a 115 bp frameshift-inducing exon in the HTT transcript. This exon is observed upon Branaplam treatment in 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 applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models.

Date: 2022
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DOI: 10.1038/s41467-022-34419-x

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