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

被引：35

作者：

Prudencio, Mercedes ^{[1
,2
]}

Garcia-Moreno, Hector ^{[3
,4
]}

Jansen-West, Karen R. ^{[1
]}

AL-Shaikh, Rana Hanna ^{[5
]}

Gendron, Tania F. ^{[1
,2
]}

Heckman, Michael G. ^{[6
]}

Spiegel, Matthew R. ^{[6
]}

Carlomagno, Yari ^{[1
,2
]}

Daughrity, Lillian M. ^{[1
]}

Song, Yuping ^{[1
]}

Dunmore, Judith A. ^{[1
]}

Byron, Natalie ^{[1
]}

Oskarsson, Bjorn ^{[5
]}

Nicholson, Katharine A. ^{[7
]}

Staff, Nathan P. ^{[8
]}

Gorcenco, Sorina ^{[9
]}

Puschmann, Andreas ^{[9
]}

Lemos, Joao ^{[10
]}

Januario, Cristina ^{[10
]}

LeDoux, Mark S. ^{[11
,12
]}

Friedman, Joseph H. ^{[13
]}

Polke, James ^{[3
,4
]}

Labrum, Robin ^{[3
,4
]}

Shakkottai, Vikram ^{[14
]}

McLoughlin, Hayley S. ^{[14
]}

Paulson, Henry L. ^{[14
]}

Konno, Takuya ^{[15
]}

Onodera, Osamu ^{[15
]}

Ikeuchi, Takeshi ^{[16
]}

Tada, Mari ^{[17
]}

Kakita, Akiyoshi ^{[17
]}

Fryer, John D. ^{[2
,18
]}

Karremo, Christin ^{[9
]}

Gomes, Ines ^{[10
]}

Caviness, John N. ^{[19
]}

Pittelkow, Mark R. ^{[20
]}

Aasly, Jan ^{[21
]}

Pfeiffer, Ronald F. ^{[22
]}

Veerappan, Venka ^{[22
]}

Eggenberger, Eric R. ^{[5
]}

Freeman, William D. ^{[5
]}

Huang, Josephine F. ^{[5
]}

Uitti, Ryan J. ^{[5
]}

Wierenga, Klaas J. ^{[5
]}

Collazo, Iris V. Marin ^{[5
]}

Tipton, Philip W. ^{[5
]}

van Gerpen, Jay A. ^{[23
]}

van Blitterswijk, Marka ^{[1
,2
]}

Bu, Guojun ^{[1
,2
]}

Wszolek, Zbigniew K. ^{[5
]}

机构：

[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Mayo Clin, Neurosci Grad Program, Grad Sch Biomed Sci, Jacksonville, FL 32224 USA

[3] UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, Ataxia Ctr, London WC1N 3BG, England

[4] Univ Coll London Hosp NHS Trust, Natl Hosp Neurol & Neurosurg, Ataxia Ctr, London WC1N 3BG, England

[5] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[6] Mayo Clin, Div Biomed Stat & Informat, Jacksonville, FL 32224 USA

[7] Massachusetts Gen Hosp MGH, Sean M Healey & AMG Ctr ALS, Boston, MA 02114 USA

[8] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA

[9] Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Neurol, S-22185 Lund, Sweden

[10] Coimbra Univ, Coimbra Univ Hosp Ctr, P-3000075 Coimbra, Portugal

[11] Univ Memphis, Memphis, TN 38152 USA

[12] Veracity Neurosci LLC, Memphis, TN 38152 USA

[13] Brown Univ, Dept Neurol, Warren Alpert Med Sch, Providence, RI 02906 USA

[14] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA

[15] Niigata Univ, Brain Res Inst, Dept Neurol, Niigata 9518585, Japan

[16] Niigata Univ, Brain Res Inst, Dept Mol Genet, Niigata 9518585, Japan

[17] Niigata Univ, Brain Res Inst, Dept Pathol, Niigata 9518585, Japan

[18] Mayo Clin, Dept Neurosci, Scottsdale, AZ 85259 USA

[19] Mayo Clin, Dept Neurol, Scottsdale, AZ 85259 USA

[20] Mayo Clin, Dept Dermatol, Scottsdale, AZ 85259 USA

[21] Norwegian Univ Sci & Technol, N-7006 Trondheim, Norway

[22] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97239 USA

[23] Univ Alabama Birmingham, Birmingham, AL 35233 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2020年 / 12卷 / 566期

关键词：

MACHADO-JOSEPH-DISEASE; CAG REPEAT; SELECTIVE INHIBITION; RNA DUPLEXES; EXPRESSION; GENE; POLYGLUTAMINE; INSTABILITY; HUNTINGTIN; SEVERITY;

D O I：

10.1126/scitranslmed.abb7086

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：11

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