2. Academic Validation
  3. Small molecule splicing modifiers with systemic HTT-lowering activity

Small molecule splicing modifiers with systemic HTT-lowering activity

  • Nat Commun. 2021 Dec 15;12(1):7299. doi: 10.1038/s41467-021-27157-z.
Anuradha Bhattacharyya 1,  Christopher R Trotta 1,  Jana Narasimhan 1,  Kari J Wiedinger 1,  Wencheng Li 1,  Kerstin A Effenberger 1,  Matthew G Woll 1,  Minakshi B Jani 1,  Nicole Risher 1,  Shirley Yeh 1,  Yaofeng Cheng 1,  Nadiya Sydorenko 1,  Young-Choon Moon 1,  Gary M Karp 1,  Marla Weetall 1,  Amal Dakka 1,  Vijayalakshmi Gabbeta 1,  Nikolai A Naryshkin 1,  Jason D Graci 1,  Thomas Tripodi Jr 1,  Amber Southwell 2,  Michael Hayden 3,  Joseph M Colacino 1,  Stuart W Peltz 4
Affiliations

Affiliations

  • 1 PTC Therapeutics, Inc. 100 Corporate Court, South Plainfield, NJ, USA.
  • 2 Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
  • 3 Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
  • 4 PTC Therapeutics, Inc. 100 Corporate Court, South Plainfield, NJ, USA. speltz@ptcbio.com.
PMID: 34911927 DOI: 10.1038/s41467-021-27157-z
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.

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