Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
| Autor: | Yari Carlomagno, Paola Giunti, Yuping Song, Bjorn Oskarsson, Jan O. Aasly, Rana Hanna Al-Shaikh, Robin Labrum, Zbigniew K. Wszolek, James M. Polke, João Lemos, Henry L. Paulson, Guojun Bu, Eric R. Eggenberger, Karen Jansen-West, William D. Freeman, Hector Garcia-Moreno, Mercedes Prudencio, Marka van Blitterswijk, Osamu Onodera, Joseph H. Friedman, Ryan J. Uitti, Inês Gomes, Hayley S. McLoughlin, Mark S. LeDoux, Takuya Konno, Venka Veerappan, Nathan P. Staff, Leonard Petrucelli, John N. Caviness, Cristina Januário, Tania F. Gendron, Lillian M. Daughrity, Mari Tada, Iris Vanessa Marin Collazo, Andreas Puschmann, Takeshi Ikeuchi, Katharine Nicholson, Josephine F. Huang, Klaas J. Wierenga, Sorina Gorcenco, Christin Karremo, Matthew R. Spiegel, Akiyoshi Kakita, Jay A. van Gerpen, Judith A. Dunmore, Ronald F. Pfeiffer, Philip W. Tipton, John D. Fryer, Mark R. Pittelkow, Vikram G. Shakkottai, Natalie Byron, Michael G. Heckman |
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| Rok vydání: | 2020 |
| Předmět: |
Neurons
congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Neurology business.industry Mutant Machado-Joseph Disease General Medicine medicine.disease Bioinformatics Article Repressor Proteins Clinical trial Polymorphism (computer science) Spinocerebellar ataxia medicine Humans Allele Ataxin-3 business Trinucleotide repeat expansion Gene Alleles |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.abb7086 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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