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Splice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat

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  • Zachariah L. McLean

    (Massachusetts General Hospital
    Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • Dadi Gao

    (Massachusetts General Hospital
    Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • Kevin Correia

    (Massachusetts General Hospital)

  • Jennie C. L. Roy

    (Massachusetts General Hospital
    Harvard Medical School)

  • Shota Shibata

    (Massachusetts General Hospital
    Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • Iris N. Farnum

    (Massachusetts General Hospital)

  • Zoe Valdepenas-Mellor

    (Massachusetts General Hospital)

  • Marina Kovalenko

    (Massachusetts General Hospital)

  • Manasa Rapuru

    (Massachusetts General Hospital)

  • Elisabetta Morini

    (Massachusetts General Hospital
    Harvard Medical School)

  • Jayla Ruliera

    (Massachusetts General Hospital)

  • Tammy Gillis

    (Massachusetts General Hospital)

  • Diane Lucente

    (Massachusetts General Hospital)

  • Benjamin P. Kleinstiver

    (Massachusetts General Hospital
    Harvard Medical School)

  • Jong-Min Lee

    (Massachusetts General Hospital
    Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • Marcy E. MacDonald

    (Massachusetts General Hospital
    Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • Vanessa C. Wheeler

    (Massachusetts General Hospital
    Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • Ricardo Mouro Pinto

    (Massachusetts General Hospital
    Harvard Medical School
    the Broad Institute of M.I.T. and Harvard)

  • James F. Gusella

    (Massachusetts General Hospital
    the Broad Institute of M.I.T. and Harvard
    Harvard Medical School)

Abstract

Huntington’s disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin’s polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic CAG repeat expansion as the driver of onset. We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Targeted CRISPR-Cas9 editing shows this effect is not due to huntingtin lowering, pointing instead to pseudoexon inclusion in PMS1. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47485-0
    DOI: 10.1038/s41467-024-47485-0
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    References listed on IDEAS

    as
    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. 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.
    3. Kendall R. Sanson & Ruth E. Hanna & Mudra Hegde & Katherine F. Donovan & Christine Strand & Meagan E. Sullender & Emma W. Vaimberg & Amy Goodale & David E. Root & Federica Piccioni & John G. Doench, 2018. "Optimized libraries for CRISPR-Cas9 genetic screens with multiple modalities," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    4. 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.
    5. Dadi Gao & Elisabetta Morini & Monica Salani & Aram J. Krauson & Anil Chekuri & Neeraj Sharma & Ashok Ragavendran & Serkan Erdin & Emily M. Logan & Wencheng Li & Amal Dakka & Jana Narasimhan & Xin Zha, 2021. "A deep learning approach to identify gene targets of a therapeutic for human splicing disorders," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
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