Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Tania D Gendron, Jeannie Chew, Jeannette N. Stankowski, Lindsey R. Hayes, Yongjie Zhang, Mercedes Prudencio, Yari Carlomagno, Lillian M. Daughrity, Karen Jansen-West, Emilie A. Perkerson, Aliesha O'Raw, Casey Cook, Luc Pregent, Veronique Belzil, Marka Van Blitterswijk, Lilia J. Tabassian, Chris W. Lee, Mei Yue, Jimei Tong, Yuping SongMonica Castanedes-Casey, Linda Rousseau, Virginia Phillips, Dennis W Dickson, Rosa V Rademakers, John D. Fryer, Beth K Rush, Otto D Pedraza, Ana M. Caputo, Pamela Desaro, Carla Palmucci, Amelia Robertson, Michael G. Heckman, Nancy N. Diehl, Edythe Wiggs, Michael Tierney, Laura Braun, Jennifer Farren, David Lacomis, Shafeeq Ladha, Christina N. Fournier, Leo F. McCluskey, Lauren B. Elman, Jon B. Toledo, Jennifer D. McBride, Cinzia Tiloca, Claudia Morelli, Barbara Poletti, Federica Solca, Alessandro Prelle, Joanne Wuu, Jennifer Jockel-Balsarotti, Frank Rigo, Christine Ambrose, Abhishek Datta, Weixing Yang, Denitza Raitcheva, Giovanna Antognetti, Alexander McCampbell, John C. Van Swieten, Bruce L. Miller, Adam L. Boxer, Robert H. Brown, Robert Bowser, Timothy M. Miller, John Q. Trojanowski, Murray Grossman, James D. Berry, William T. Hu, Antonia Ratti, Bryan J. Traynor, Matthew D. Disney, Michael Benatar, Vincenzo Silani, Jonathan D. Glass, Mary Kay Floeter, Jeffrey D. Rothstein, Kevin B. Boylan, Leonard Petrucelli

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Article numbereaai7866
JournalScience Translational Medicine
Volume9
Issue number383
DOIs
StatePublished - Mar 29 2017

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Amyotrophic Lateral Sclerosis
RNA
Proteins
Antisense Oligonucleotides
Therapeutics
Cerebrospinal Fluid
Cerebrospinal Fluid Proteins
Motor Neuron Disease
Dipeptides
Blood Cells
Clinical Trials
Mutation
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. / Gendron, Tania D; Chew, Jeannie; Stankowski, Jeannette N.; Hayes, Lindsey R.; Zhang, Yongjie; Prudencio, Mercedes; Carlomagno, Yari; Daughrity, Lillian M.; Jansen-West, Karen; Perkerson, Emilie A.; O'Raw, Aliesha; Cook, Casey; Pregent, Luc; Belzil, Veronique; Van Blitterswijk, Marka; Tabassian, Lilia J.; Lee, Chris W.; Yue, Mei; Tong, Jimei; Song, Yuping; Castanedes-Casey, Monica; Rousseau, Linda; Phillips, Virginia; Dickson, Dennis W; Rademakers, Rosa V; Fryer, John D.; Rush, Beth K; Pedraza, Otto D; Caputo, Ana M.; Desaro, Pamela; Palmucci, Carla; Robertson, Amelia; Heckman, Michael G.; Diehl, Nancy N.; Wiggs, Edythe; Tierney, Michael; Braun, Laura; Farren, Jennifer; Lacomis, David; Ladha, Shafeeq; Fournier, Christina N.; McCluskey, Leo F.; Elman, Lauren B.; Toledo, Jon B.; McBride, Jennifer D.; Tiloca, Cinzia; Morelli, Claudia; Poletti, Barbara; Solca, Federica; Prelle, Alessandro; Wuu, Joanne; Jockel-Balsarotti, Jennifer; Rigo, Frank; Ambrose, Christine; Datta, Abhishek; Yang, Weixing; Raitcheva, Denitza; Antognetti, Giovanna; McCampbell, Alexander; Van Swieten, John C.; Miller, Bruce L.; Boxer, Adam L.; Brown, Robert H.; Bowser, Robert; Miller, Timothy M.; Trojanowski, John Q.; Grossman, Murray; Berry, James D.; Hu, William T.; Ratti, Antonia; Traynor, Bryan J.; Disney, Matthew D.; Benatar, Michael; Silani, Vincenzo; Glass, Jonathan D.; Floeter, Mary Kay; Rothstein, Jeffrey D.; Boylan, Kevin B.; Petrucelli, Leonard.

In: Science Translational Medicine, Vol. 9, No. 383, eaai7866, 29.03.2017.

Research output: Contribution to journalArticle

Gendron, TD, Chew, J, Stankowski, JN, Hayes, LR, Zhang, Y, Prudencio, M, Carlomagno, Y, Daughrity, LM, Jansen-West, K, Perkerson, EA, O'Raw, A, Cook, C, Pregent, L, Belzil, V, Van Blitterswijk, M, Tabassian, LJ, Lee, CW, Yue, M, Tong, J, Song, Y, Castanedes-Casey, M, Rousseau, L, Phillips, V, Dickson, DW, Rademakers, RV, Fryer, JD, Rush, BK, Pedraza, OD, Caputo, AM, Desaro, P, Palmucci, C, Robertson, A, Heckman, MG, Diehl, NN, Wiggs, E, Tierney, M, Braun, L, Farren, J, Lacomis, D, Ladha, S, Fournier, CN, McCluskey, LF, Elman, LB, Toledo, JB, McBride, JD, Tiloca, C, Morelli, C, Poletti, B, Solca, F, Prelle, A, Wuu, J, Jockel-Balsarotti, J, Rigo, F, Ambrose, C, Datta, A, Yang, W, Raitcheva, D, Antognetti, G, McCampbell, A, Van Swieten, JC, Miller, BL, Boxer, AL, Brown, RH, Bowser, R, Miller, TM, Trojanowski, JQ, Grossman, M, Berry, JD, Hu, WT, Ratti, A, Traynor, BJ, Disney, MD, Benatar, M, Silani, V, Glass, JD, Floeter, MK, Rothstein, JD, Boylan, KB & Petrucelli, L 2017, 'Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis', Science Translational Medicine, vol. 9, no. 383, eaai7866. https://doi.org/10.1126/scitranslmed.aai7866
Gendron, Tania D ; Chew, Jeannie ; Stankowski, Jeannette N. ; Hayes, Lindsey R. ; Zhang, Yongjie ; Prudencio, Mercedes ; Carlomagno, Yari ; Daughrity, Lillian M. ; Jansen-West, Karen ; Perkerson, Emilie A. ; O'Raw, Aliesha ; Cook, Casey ; Pregent, Luc ; Belzil, Veronique ; Van Blitterswijk, Marka ; Tabassian, Lilia J. ; Lee, Chris W. ; Yue, Mei ; Tong, Jimei ; Song, Yuping ; Castanedes-Casey, Monica ; Rousseau, Linda ; Phillips, Virginia ; Dickson, Dennis W ; Rademakers, Rosa V ; Fryer, John D. ; Rush, Beth K ; Pedraza, Otto D ; Caputo, Ana M. ; Desaro, Pamela ; Palmucci, Carla ; Robertson, Amelia ; Heckman, Michael G. ; Diehl, Nancy N. ; Wiggs, Edythe ; Tierney, Michael ; Braun, Laura ; Farren, Jennifer ; Lacomis, David ; Ladha, Shafeeq ; Fournier, Christina N. ; McCluskey, Leo F. ; Elman, Lauren B. ; Toledo, Jon B. ; McBride, Jennifer D. ; Tiloca, Cinzia ; Morelli, Claudia ; Poletti, Barbara ; Solca, Federica ; Prelle, Alessandro ; Wuu, Joanne ; Jockel-Balsarotti, Jennifer ; Rigo, Frank ; Ambrose, Christine ; Datta, Abhishek ; Yang, Weixing ; Raitcheva, Denitza ; Antognetti, Giovanna ; McCampbell, Alexander ; Van Swieten, John C. ; Miller, Bruce L. ; Boxer, Adam L. ; Brown, Robert H. ; Bowser, Robert ; Miller, Timothy M. ; Trojanowski, John Q. ; Grossman, Murray ; Berry, James D. ; Hu, William T. ; Ratti, Antonia ; Traynor, Bryan J. ; Disney, Matthew D. ; Benatar, Michael ; Silani, Vincenzo ; Glass, Jonathan D. ; Floeter, Mary Kay ; Rothstein, Jeffrey D. ; Boylan, Kevin B. ; Petrucelli, Leonard. / Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. In: Science Translational Medicine. 2017 ; Vol. 9, No. 383.
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title = "Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis",
abstract = "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",
author = "Gendron, {Tania D} and Jeannie Chew and Stankowski, {Jeannette N.} and Hayes, {Lindsey R.} and Yongjie Zhang and Mercedes Prudencio and Yari Carlomagno and Daughrity, {Lillian M.} and Karen Jansen-West and Perkerson, {Emilie A.} and Aliesha O'Raw and Casey Cook and Luc Pregent and Veronique Belzil and {Van Blitterswijk}, Marka and Tabassian, {Lilia J.} and Lee, {Chris W.} and Mei Yue and Jimei Tong and Yuping Song and Monica Castanedes-Casey and Linda Rousseau and Virginia Phillips and Dickson, {Dennis W} and Rademakers, {Rosa V} and Fryer, {John D.} and Rush, {Beth K} and Pedraza, {Otto D} and Caputo, {Ana M.} and Pamela Desaro and Carla Palmucci and Amelia Robertson and Heckman, {Michael G.} and Diehl, {Nancy N.} and Edythe Wiggs and Michael Tierney and Laura Braun and Jennifer Farren and David Lacomis and Shafeeq Ladha and Fournier, {Christina N.} and McCluskey, {Leo F.} and Elman, {Lauren B.} and Toledo, {Jon B.} and McBride, {Jennifer D.} and Cinzia Tiloca and Claudia Morelli and Barbara Poletti and Federica Solca and Alessandro Prelle and Joanne Wuu and Jennifer Jockel-Balsarotti and Frank Rigo and Christine Ambrose and Abhishek Datta and Weixing Yang and Denitza Raitcheva and Giovanna Antognetti and Alexander McCampbell and {Van Swieten}, {John C.} and Miller, {Bruce L.} and Boxer, {Adam L.} and Brown, {Robert H.} and Robert Bowser and Miller, {Timothy M.} and Trojanowski, {John Q.} and Murray Grossman and Berry, {James D.} and Hu, {William T.} and Antonia Ratti and Traynor, {Bryan J.} and Disney, {Matthew D.} and Michael Benatar and Vincenzo Silani and Glass, {Jonathan D.} and Floeter, {Mary Kay} and Rothstein, {Jeffrey D.} and Boylan, {Kevin B.} and Leonard Petrucelli",
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T1 - Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

AU - Gendron, Tania D

AU - Chew, Jeannie

AU - Stankowski, Jeannette N.

AU - Hayes, Lindsey R.

AU - Zhang, Yongjie

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 V

AU - Fryer, John D.

AU - Rush, Beth K

AU - Pedraza, Otto D

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

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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

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