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

Prudencio, Mercedes ; Garcia-Moreno, Hector ; Jansen-West, Karen R ; Al-Shaikh, Rana Hanna ; Gendron, Tania F ; Heckman, Michael G ; Spiegel, Matthew R ; Carlomagno, Yari ; Daughrity, Lillian M and Song, Yuping , et al. (2020) In Science Translational Medicine 12(566).
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... (More)

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.

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organization
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Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
12
issue
566
article number
eabb7086
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:33087504
  • scopus:85094162986
ISSN
1946-6242
DOI
10.1126/scitranslmed.abb7086
language
English
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yes
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Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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42b36459-f626-480d-a0be-379b916b24ed
date added to LUP
2020-11-02 10:44:08
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2021-04-06 04:45:09
@article{42b36459-f626-480d-a0be-379b916b24ed,
  abstract     = {<p>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.</p>},
  author       = {Prudencio, Mercedes and Garcia-Moreno, Hector and Jansen-West, Karen R and Al-Shaikh, Rana Hanna and Gendron, Tania F and Heckman, Michael G and Spiegel, Matthew R and Carlomagno, Yari and Daughrity, Lillian M and Song, Yuping and Dunmore, Judith A and Byron, Natalie and Oskarsson, Björn and Nicholson, Katharine A and Staff, Nathan P and Gorcenco, Sorina and Puschmann, Andreas and Lemos, João and Januário, Cristina and LeDoux, Mark S and Friedman, Joseph H and Polke, James and Labrum, Robin and Shakkottai, Vikram and McLoughlin, Hayley S and Paulson, Henry L and Konno, Takuya and Onodera, Osamu and Ikeuchi, Takeshi and Tada, Mari and Kakita, Akiyoshi and Fryer, John D and Karremo, Christin and Gomes, Inês and Caviness, John N and Pittelkow, Mark R and Aasly, Jan and Pfeiffer, Ronald F and Veerappan, Venka and Eggenberger, Eric R and Freeman, William D and Huang, Josephine F and Uitti, Ryan J and Wierenga, Klaas J and Marin Collazo, Iris V and Tipton, Philip W and van Gerpen, Jay A and van Blitterswijk, Marka and Bu, Guojun and Wszolek, Zbigniew K and Petrucelli, Leonard},
  issn         = {1946-6242},
  language     = {eng},
  month        = {10},
  number       = {566},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3},
  url          = {http://dx.doi.org/10.1126/scitranslmed.abb7086},
  doi          = {10.1126/scitranslmed.abb7086},
  volume       = {12},
  year         = {2020},
}