Krach, Florian and Stemick, Judith and Boerstler, Tom and Weiss, Alexander and Lingos, Ioannis and Reischl, Stephanie and Meixner, Holger and Ploetz, Sonja and Farrell, Michaela and Hehr, Ute and Kohl, Zacharias and Winner, Beate and Winkler, Juergen (2022) An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons. NATURE COMMUNICATIONS, 13 (1): 6797. ISSN , 2041-1723
Full text not available from this repository. (Request a copy)Abstract
Krach et al. dissect the molecular mechanism of the alternative splicing modulator Branaplam in Huntington's disease. They show that the drug lowers mutant HTT protein levels and ameliorates alternative splicing pathology in an iPSC disease model. 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CEREBROSPINAL-FLUID; CEREBRAL-CORTEX; CELL LOSS; MOTOR; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Feb 2024 13:58 |
| Last Modified: | 27 Feb 2024 13:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57925 |
Actions (login required)
 |
View Item |
