IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-28653-6.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-28653-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-28653-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jonathan P. Ling & Alexei M. Bygrave & Clayton P. Santiago & Rogger P. Carmen-Orozco & Vickie T. Trinh & Minzhong Yu & Yini Li & Ying Liu & Kyra D. Bowden & Leighton H. Duncan & Jeong Han & Kamil Tane, 2022. "Cell-specific regulation of gene expression using splicing-dependent frameshifting," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Asmundur Oddsson & Patrick Sulem & Gardar Sveinbjornsson & Gudny A. Arnadottir & Valgerdur Steinthorsdottir & Gisli H. Halldorsson & Bjarni A. Atlason & Gudjon R. Oskarsson & Hannes Helgason & Henriet, 2023. "Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    4. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Laura M. Mueller & Abigail Isaacson & Heather Wilson & Anna Salowka & Isabel Tay & Maolian Gong & Nancy Samir Elbarbary & Klemens Raile & Francesca M. Spagnoli, 2024. "Heterozygous missense variant in GLI2 impairs human endocrine pancreas development," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Alexendar R. Perez & Laura Sala & Richard K. Perez & Joana A. Vidigal, 2021. "CSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    7. Kian Hong Kock & Patrick K. Kimes & Stephen S. Gisselbrecht & Sachi Inukai & Sabrina K. Phanor & James T. Anderson & Gayatri Ramakrishnan & Colin H. Lipper & Dongyuan Song & Jesse V. Kurland & Julia M, 2024. "DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    8. Gaëlle Odelin & Adèle Faucherre & Damien Marchese & Amélie Pinard & Hager Jaouadi & Solena Scouarnec & Raphaël Chiarelli & Younes Achouri & Emilie Faure & Marine Herbane & Alexis Théron & Jean-Françoi, 2023. "Variations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Matthew Tegtmeyer & Jatin Arora & Samira Asgari & Beth A. Cimini & Ajay Nadig & Emily Peirent & Dhara Liyanage & Gregory P. Way & Erin Weisbart & Aparna Nathan & Tiffany Amariuta & Kevin Eggan & Marzi, 2024. "High-dimensional phenotyping to define the genetic basis of cellular morphology," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    10. Erik Schoenmakers & Federica Marelli & Helle F. Jørgensen & W. Edward Visser & Carla Moran & Stefan Groeneweg & Carolina Avalos & Sean J. Jurgens & Nichola Figg & Alison Finigan & Neha Wali & Maura Ag, 2023. "Selenoprotein deficiency disorder predisposes to aortic aneurysm formation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    11. Sarah E. Garnish & Katherine R. Martin & Maria Kauppi & Victoria E. Jackson & Rebecca Ambrose & Vik Ven Eng & Shene Chiou & Yanxiang Meng & Daniel Frank & Emma C. Tovey Crutchfield & Komal M. Patel & , 2023. "A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    12. Matthew J. O’Neill & Tao Yang & Julie Laudeman & Maria E. Calandranis & M. Lorena Harvey & Joseph F. Solus & Dan M. Roden & Andrew M. Glazer, 2024. "ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    13. Xiaoyi Raymond Gao & Marion Chiariglione & Alexander J. Arch, 2022. "Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    14. Shaan Khurshid & Julieta Lazarte & James P. Pirruccello & Lu-Chen Weng & Seung Hoan Choi & Amelia W. Hall & Xin Wang & Samuel F. Friedman & Victor Nauffal & Kiran J. Biddinger & Krishna G. Aragam & Pu, 2023. "Clinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    15. Javier Rodríguez-Ubreva & Anna Arutyunyan & Marc Jan Bonder & Lucía Del Pino-Molina & Stephen J. Clark & Carlos de la Calle-Fabregat & Luz Garcia-Alonso & Louis-François Handfield & Laura Ciudad & Edu, 2022. "Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    16. Michel S. Naslavsky & Marilia O. Scliar & Guilherme L. Yamamoto & Jaqueline Yu Ting Wang & Stepanka Zverinova & Tatiana Karp & Kelly Nunes & José Ricardo Magliocco Ceroni & Diego Lima Carvalho & Carlo, 2022. "Whole-genome sequencing of 1,171 elderly admixed individuals from Brazil," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    17. Nicole Deflaux & Margaret Sunitha Selvaraj & Henry Robert Condon & Kelsey Mayo & Sara Haidermota & Melissa A. Basford & Chris Lunt & Anthony A. Philippakis & Dan M. Roden & Joshua C. Denny & Anjene Mu, 2023. "Demonstrating paths for unlocking the value of cloud genomics through cross cohort analysis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    18. Andrea Wilderman & Eva D’haene & Machteld Baetens & Tara N. Yankee & Emma Wentworth Winchester & Nicole Glidden & Ellen Roets & Jo Dorpe & Sandra Janssens & Danny E. Miller & Miranda Galey & Kari M. B, 2024. "A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    19. Ruoyu Tian & Tian Ge & Hyeokmoon Kweon & Daniel B. Rocha & Max Lam & Jimmy Z. Liu & Kritika Singh & Daniel F. Levey & Joel Gelernter & Murray B. Stein & Ellen A. Tsai & Hailiang Huang & Christopher F., 2024. "Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    20. Iker Núñez-Carpintero & Maria Rigau & Mattia Bosio & Emily O’Connor & Sally Spendiff & Yoshiteru Azuma & Ana Topf & Rachel Thompson & Peter A. C. ’t Hoen & Teodora Chamova & Ivailo Tournev & Velina Gu, 2024. "Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28653-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.