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

Autor:	Prudencio M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA., Garcia-Moreno H; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; Ataxia Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Trust, London WC1N 3BG, UK., Jansen-West KR; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Al-Shaikh RH; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Gendron TF; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA., Heckman MG; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, USA., Spiegel MR; Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, USA., Carlomagno Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA., Daughrity LM; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Song Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Dunmore JA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Byron N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Oskarsson B; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Nicholson KA; Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital (MGH), Boston, MA 02114, USA., Staff NP; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA., Gorcenco S; Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund 22185, Sweden., Puschmann A; Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund 22185, Sweden., Lemos J; Coimbra University Hospital Centre, Coimbra University, Coimbra 3000-075, Portugal., Januário C; Coimbra University Hospital Centre, Coimbra University, Coimbra 3000-075, Portugal., LeDoux MS; University of Memphis and Veracity Neuroscience LLC, Memphis, TN 38152, USA., Friedman JH; Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI 02906, USA., Polke J; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; Ataxia Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Trust, London WC1N 3BG, UK., Labrum R; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.; Ataxia Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Trust, London WC1N 3BG, UK., Shakkottai V; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA., McLoughlin HS; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA., Paulson HL; Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA., Konno T; Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan., Onodera O; Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan., Ikeuchi T; Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata 951-8585, Japan., Tada M; Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan., Kakita A; Department of Pathology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan., Fryer JD; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA.; Department of Neuroscience, Mayo Clinic, Scottsdale, AZ 85259, USA., Karremo C; Lund University, Skåne University Hospital, Department of Clinical Sciences Lund, Neurology, Lund 22185, Sweden., Gomes I; Coimbra University Hospital Centre, Coimbra University, Coimbra 3000-075, Portugal., Caviness JN; Department of Neurology, Mayo Clinic, Scottsdale, AZ 85259, USA., Pittelkow MR; Department of Dermatology, Mayo Clinic, Scottsdale, AZ 85259, USA., Aasly J; Norwegian University of Science and Technology, 7006 Trondheim, Norway., Pfeiffer RF; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA., Veerappan V; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA., Eggenberger ER; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Freeman WD; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Huang JF; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Uitti RJ; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Wierenga KJ; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Marin Collazo IV; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Tipton PW; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., van Gerpen JA; University of Alabama at Birmingham, Birmingham, AL 35233, USA., van Blitterswijk M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA., Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA., Wszolek ZK; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA. wszolek.zbigniew@mayo.edu p.giunti@ucl.ac.uk petrucelli.leonard@mayo.edu., Giunti P; Ataxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK. wszolek.zbigniew@mayo.edu p.giunti@ucl.ac.uk petrucelli.leonard@mayo.edu.; Ataxia Centre, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Trust, London WC1N 3BG, UK., Petrucelli L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. wszolek.zbigniew@mayo.edu p.giunti@ucl.ac.uk petrucelli.leonard@mayo.edu.; Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2020 Oct 21; Vol. 12 (566).
DOI:	10.1126/scitranslmed.abb7086
Abstrakt:	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. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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