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

Author

Listed:
  • Caroline Gubser Keller

    (Novartis Institutes for Biomedical Research)

  • Youngah Shin

    (Novartis Institutes for Biomedical Research)

  • Alex Mas Monteys

    (The Children’s Hospital of Philadelphia
    The University of Pennsylvania)

  • 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
    The University of Pennsylvania)

  • Rajeev Sivasankaran

    (Novartis Institutes for Biomedical Research)

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.

Suggested Citation

  • 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 Re, 2022. "An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28653-6
    DOI: 10.1038/s41467-022-28653-6
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    References listed on IDEAS

    as
    1. Alex Mas Monteys & Amiel A. Hundley & Paul T. Ranum & Luis Tecedor & Amy Muehlmatt & Euyn Lim & Dmitriy Lukashev & Rajeev Sivasankaran & Beverly L. Davidson, 2021. "Regulated control of gene therapies by drug-induced splicing," Nature, Nature, vol. 596(7871), pages 291-295, August.
    2. Daichi Inoue & Guo-Liang Chew & Bo Liu & Brittany C. Michel & Joseph Pangallo & Andrew R. D’Avino & Tyler Hitchman & Khrystyna North & Stanley Chun-Wei Lee & Lillian Bitner & Ariele Block & Amanda R. , 2019. "Spliceosomal disruption of the non-canonical BAF complex in cancer," Nature, Nature, vol. 574(7778), pages 432-436, October.
    3. Konrad J. Karczewski & Laurent C. Francioli & Grace Tiao & Beryl B. Cummings & Jessica Alföldi & Qingbo Wang & Ryan L. Collins & Kristen M. Laricchia & Andrea Ganna & Daniel P. Birnbaum & Laura D. Gau, 2020. "The mutational constraint spectrum quantified from variation in 141,456 humans," Nature, Nature, vol. 581(7809), pages 434-443, May.
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    Cited by:

    1. Florian Krach & Judith Stemick & Tom Boerstler & Alexander Weiss & Ioannis Lingos & Stephanie Reischl & Holger Meixner & Sonja Ploetz & Michaela Farrell & Ute Hehr & Zacharias Kohl & Beate Winner & Ju, 2022. "An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Yuma Ishigami & Mandy S. Wong & Carlos Martí-Gómez & Andalus Ayaz & Mahdi Kooshkbaghi & Sonya M. Hanson & David M. McCandlish & Adrian R. Krainer & Justin B. Kinney, 2024. "Specificity, synergy, and mechanisms of splice-modifying drugs," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Zachariah L. McLean & Dadi Gao & Kevin Correia & Jennie C. L. Roy & Shota Shibata & Iris N. Farnum & Zoe Valdepenas-Mellor & Marina Kovalenko & Manasa Rapuru & Elisabetta Morini & Jayla Ruliera & Tamm, 2024. "Splice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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