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Small molecule splicing modifiers with systemic HTT-lowering activity

Author

Listed:
  • Anuradha Bhattacharyya

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Christopher R. Trotta

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Jana Narasimhan

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Kari J. Wiedinger

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Wencheng Li

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Kerstin A. Effenberger

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Matthew G. Woll

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Minakshi B. Jani

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Nicole Risher

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Shirley Yeh

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Yaofeng Cheng

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Nadiya Sydorenko

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Young-Choon Moon

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Gary M. Karp

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Marla Weetall

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Amal Dakka

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Vijayalakshmi Gabbeta

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Nikolai A. Naryshkin

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Jason D. Graci

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Thomas Tripodi

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Amber Southwell

    (Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida)

  • Michael Hayden

    (University of British Columbia)

  • Joseph M. Colacino

    (PTC Therapeutics, Inc. 100 Corporate Court)

  • Stuart W. Peltz

    (PTC Therapeutics, Inc. 100 Corporate Court)

Abstract

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressing HTT transcription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lower HTT expression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading to HTT mRNA degradation and reduction of HTT levels.

Suggested Citation

  • Anuradha Bhattacharyya & Christopher R. Trotta & Jana Narasimhan & Kari J. Wiedinger & Wencheng Li & Kerstin A. Effenberger & Matthew G. Woll & Minakshi B. Jani & Nicole Risher & Shirley Yeh & Yaofeng, 2021. "Small molecule splicing modifiers with systemic HTT-lowering activity," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27157-z
    DOI: 10.1038/s41467-021-27157-z
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