Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3

Research output: Contribution to journalArticle

Abstract

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Details

Authors
  • Mercedes Prudencio
  • Hector Garcia-Moreno
  • Karen R Jansen-West
  • Rana Hanna Al-Shaikh
  • Tania F Gendron
  • Michael G Heckman
  • Matthew R Spiegel
  • Yari Carlomagno
  • Lillian M Daughrity
  • Yuping Song
  • Judith A Dunmore
  • Natalie Byron
  • Björn Oskarsson
  • Katharine A Nicholson
  • Nathan P Staff
  • Sorina Gorcenco
  • Andreas Puschmann
  • João Lemos
  • Cristina Januário
  • Mark S LeDoux
  • Joseph H Friedman
  • James Polke
  • Robin Labrum
  • Vikram Shakkottai
  • Hayley S McLoughlin
  • Henry L Paulson
  • Takuya Konno
  • Osamu Onodera
  • Takeshi Ikeuchi
  • Mari Tada
  • Akiyoshi Kakita
  • John D Fryer
  • Christin Karremo
  • Inês Gomes
  • John N Caviness
  • Mark R Pittelkow
  • Jan Aasly
  • Ronald F Pfeiffer
  • Venka Veerappan
  • Eric R Eggenberger
  • William D Freeman
  • Josephine F Huang
  • Ryan J Uitti
  • Klaas J Wierenga
  • Iris V Marin Collazo
  • Philip W Tipton
  • Jay A van Gerpen
  • Marka van Blitterswijk
  • Guojun Bu
  • Zbigniew K Wszolek
  • Leonard Petrucelli
  • et al.
Organisations
External organisations
  • Nordsjællands Hospital
  • Mayo Clinic Minnesota
  • Skåne University Hospital
  • Center for Neuroscience and Cell Biology, University of Coimbra
  • Western Michigan University
  • Niigata University
  • Norwegian University of Science and Technology
  • Oregon Health & Science University
  • University of South Alabama
  • Mayo Clinic Florida
  • University of Géneve, Department of Clinical Neuroscience
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology
Original languageEnglish
Article numbereabb7086
JournalScience Translational Medicine
Volume12
Issue number566
Publication statusPublished - 2020 Oct 21
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.