Small molecule splicing modifiers with systemic HTT-lowering activity

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 Cheng, Nadiya Sydorenko, Young-Choon Moon, Gary M. Karp, Marla Weetall, Amal Dakka, Vijayalakshmi Gabbeta, Nikolai A. Naryshkin, Jason D. Graci, Thomas Tripodi, Amber Southwell, Michael Hayden, Joseph M. Colacino and Stuart W. Peltz ()
Additional contact information
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

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27157-z

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