An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion

Caroline Gubser Keller, Youngah Shin, Alex Mas Monteys, Nicole Renaud, Martin Beibel, Natalia Teider, Thomas Peters, Thomas Faller, Sophie St-Cyr, Judith Knehr, Guglielmo Roma, Alejandro Reyes, Marc Hild, Dmitriy Lukashev, Diethilde Theil, Natalie Dales, Jang-Ho Cha, Beth Borowsky, Ricardo Dolmetsch, Beverly L. Davidson () and Rajeev Sivasankaran ()
Additional contact information
Caroline Gubser Keller: Novartis Institutes for Biomedical Research
Youngah Shin: Novartis Institutes for Biomedical Research
Alex Mas Monteys: The Children’s Hospital of Philadelphia
Nicole Renaud: Novartis Institutes for Biomedical Research
Martin Beibel: Novartis Institutes for Biomedical Research
Natalia Teider: Novartis Institutes for Biomedical Research
Thomas Peters: Novartis Institutes for Biomedical Research
Thomas Faller: Novartis Institutes for Biomedical Research
Sophie St-Cyr: The Children’s Hospital of Philadelphia
Judith Knehr: Novartis Institutes for Biomedical Research
Guglielmo Roma: Novartis Institutes for Biomedical Research
Alejandro Reyes: Novartis Institutes for Biomedical Research
Marc Hild: Novartis Institutes for Biomedical Research
Dmitriy Lukashev: Novartis Institutes for Biomedical Research
Diethilde Theil: Novartis Institutes for Biomedical Research
Natalie Dales: Novartis Institutes for Biomedical Research
Jang-Ho Cha: Novartis Institutes for Biomedical Research
Beth Borowsky: Novartis Pharmaceuticals
Ricardo Dolmetsch: Novartis Institutes for Biomedical Research
Beverly L. Davidson: The Children’s Hospital of Philadelphia
Rajeev Sivasankaran: Novartis Institutes for Biomedical Research

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam’s utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion.

Date: 2022
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DOI: 10.1038/s41467-022-28653-6

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