TY - JOUR
T1 - Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis
AU - Gendron, Tania F.
AU - Chew, Jeannie
AU - Stankowski, Jeannette N.
AU - Hayes, Lindsey R.
AU - Zhang, Yong Jie
AU - Prudencio, Mercedes
AU - Carlomagno, Yari
AU - Daughrity, Lillian M.
AU - Jansen-West, Karen
AU - Perkerson, Emilie A.
AU - O'Raw, Aliesha
AU - Cook, Casey
AU - Pregent, Luc
AU - Belzil, Veronique
AU - Van Blitterswijk, Marka
AU - Tabassian, Lilia J.
AU - Lee, Chris W.
AU - Yue, Mei
AU - Tong, Jimei
AU - Song, Yuping
AU - Castanedes-Casey, Monica
AU - Rousseau, Linda
AU - Phillips, Virginia
AU - Dickson, Dennis W.
AU - Rademakers, Rosa
AU - Fryer, John D.
AU - Rush, Beth K.
AU - Pedraza, Otto
AU - Caputo, Ana M.
AU - Desaro, Pamela
AU - Palmucci, Carla
AU - Robertson, Amelia
AU - Heckman, Michael G.
AU - Diehl, Nancy N.
AU - Wiggs, Edythe
AU - Tierney, Michael
AU - Braun, Laura
AU - Farren, Jennifer
AU - Lacomis, David
AU - Ladha, Shafeeq
AU - Fournier, Christina N.
AU - McCluskey, Leo F.
AU - Elman, Lauren B.
AU - Toledo, Jon B.
AU - McBride, Jennifer D.
AU - Tiloca, Cinzia
AU - Morelli, Claudia
AU - Poletti, Barbara
AU - Solca, Federica
AU - Prelle, Alessandro
AU - Wuu, Joanne
AU - Jockel-Balsarotti, Jennifer
AU - Rigo, Frank
AU - Ambrose, Christine
AU - Datta, Abhishek
AU - Yang, Weixing
AU - Raitcheva, Denitza
AU - Antognetti, Giovanna
AU - McCampbell, Alexander
AU - Van Swieten, John C.
AU - Miller, Bruce L.
AU - Boxer, Adam L.
AU - Brown, Robert H.
AU - Bowser, Robert
AU - Miller, Timothy M.
AU - Trojanowski, John Q.
AU - Grossman, Murray
AU - Berry, James D.
AU - Hu, William T.
AU - Ratti, Antonia
AU - Traynor, Bryan J.
AU - Disney, Matthew D.
AU - Benatar, Michael
AU - Silani, Vincenzo
AU - Glass, Jonathan D.
AU - Floeter, Mary Kay
AU - Rothstein, Jeffrey D.
AU - Boylan, Kevin B.
AU - Petrucelli, Leonard
N1 - Funding Information:
This work was supported by the NIH/National Institute on Aging (P01AG017586 to M.G. and J.Q.T., K23AG042856 to W.T.H., and AG10124 to J.Q.T.), the NIH/National Institute of Neurological Disorders and Stroke (R21NS089979 to K.B.B. and T.F.G.; R25NS065729 to L.R.H.; R01NS078398 to T.M.M.; R35NS097273 to L. Petrucelli; R21NS084528 to L. Petrucelli; P01NS084974 to L. Petrucelli, D.W.D., K.B.B., and R.R.; R01NS088689 to R.H.B. and L. Petrucelli; and R01NS085207 and U54NS091046 to J.D.R.), the intramural research program of the NIH/National Institute of Neurological Disorders and Stroke (Z01NS003146 to M.K.F.), the U.S. Department of Defense (Amyotrophic Lateral Sclerosis Research Program AL130125 to L. Petrucelli), Mayo Clinic Foundation (to L. Petrucelli), Mayo Clinic Center for Individualized Medicine (to K.B.B., T.F.G., and L. Petrucelli), Amyotrophic Lateral Sclerosis Association (to K.B.B., M.B., J.D.G., T.F.G., L.R.H., L. Petrucelli, M.P., J.W., and Y.-J.Z.), the Robert Packard Center for ALS Research at Johns Hopkins (to J.D.R. and L. Petrucelli), Target ALS (to J.D.R. and L. Petrucelli), Association for Frontotemporal Degeneration (to L. Petrucelli), Biogen (to L. Petrucelli), the ALS Therapy Alliance (to J.D.B. and J.D.G), ALS Finding A Cure Foundation (to J.D.B.), the Brain Science Institute (to J.D.R.), the Muscular Dystrophy Association (#416137 to T.F.G.; #4365 and #172123 to M.B. and J.W.), the Italian Ministry of Health (RF-2013-02355764 to C.T., C.M., B.P., F.S., A. Ratti, and V.S.) and STRENGTH project funded by EU Joint Programme-Neurodegenerative Disease Research (to C.T., C.M., B.P., A. Ratti, and V.S.), and Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) (U54-NS-092091 to M.B. and J.W.) and Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) (U54-NS-092089 to A.L.B.) consortia, which are part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS). CReATe and ARTFL are funded through a collaboration between NCATS and National Institute of Neurological Disorders and Stroke.
Publisher Copyright:
© The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2017/3/29
Y1 - 2017/3/29
N2 - There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention. 2017
AB - There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention. 2017
UR - http://www.scopus.com/inward/record.url?scp=85017408763&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017408763&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aai7866
DO - 10.1126/scitranslmed.aai7866
M3 - Article
C2 - 28356511
AN - SCOPUS:85017408763
SN - 1946-6234
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 383
M1 - eaai7866
ER -