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

Yuping Song; Monica Castanedes-Casey; Linda Rousseau; Virginia Phillips; Dennis W Dickson; Rosa Rademakers; John D Fryer; Beth K Rush; Otto 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; Tania F Gendron; Bruce L Miller; Jeannie Chew; Adam L Boxer; Jeannette N Stankowski; Robert H Brown; Lindsey R Hayes; Robert Bowser; Timothy M Miller; Yong-Jie Zhang; Mercedes Prudencio; John Q Trojanowski; Yari Carlomagno; Murray Grossman; James D Berry; Lillian M Daughrity; Karen Jansen-West; William T Hu; Antonia Ratti; Emilie A Perkerson; Aliesha O'Raw; Bryan J Traynor; Casey Cook; Matthew D Disney; Luc Pregent; Michael Benatar; Veronique Belzil; Vincenzo Silani; Marka van Blitterswijk; Jonathan D Glass; Lilia J Tabassian; Mary Kay Floeter; Chris W Lee; Jeffrey D Rothstein; Mei Yue; Kevin B Boylan; Jimei Tong; Leonard Petrucelli

doi:10.1126/scitranslmed.aai7866

Back

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

Journal article

Open access

Peer reviewed

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

Yuping Song, Monica Castanedes-Casey, Linda Rousseau, Virginia Phillips, Dennis W Dickson, Rosa Rademakers, John D Fryer, Beth K Rush, Otto Pedraza, Ana M Caputo, …

Science translational medicine, Vol.9(383), pp.eaai7866-eaai7866

2017-03-29

DOI: https://doi.org/10.1126/scitranslmed.aai7866

PMCID: PMC5576451

PMID: 28356511

Abstract

Biomarkers - metabolism

C9orf72 Protein - genetics

Cell Line

Leukocytes, Mononuclear - metabolism

Leukocytes, Mononuclear - drug effects

Oligonucleotides, Antisense - pharmacology

Prognosis

Induced Pluripotent Stem Cells - drug effects

Amyotrophic Lateral Sclerosis - genetics

Humans

Middle Aged

Dinucleotide Repeats - genetics

RNA - genetics

Brain - metabolism

Amyotrophic Lateral Sclerosis - pathology

Animals

Amyotrophic Lateral Sclerosis - cerebrospinal fluid

Brain - pathology

Adult

Aged

Mice

Neurons - metabolism

Longitudinal Studies

Induced Pluripotent Stem Cells - metabolism

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G C repeat expansion in the gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G C repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in -associated ALS (c9ALS). Therapeutics that target G C 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 G C 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 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 G C RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G C RNA and downstream G C RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G C RNA-based therapies in symptomatic repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Files and links (1)

url

https://doi.org/10.1126/scitranslmed.aai7866View

Published (Version of record) Open

Metrics

101 Record Views

154 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.765 Amyotrophic Lateral Sclerosis
Web Of Science research areas: Cell Biology; Medicine, Research & Experimental
ESI research areas: Biology & Biochemistry

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites

Details

Title: Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72 -associated amyotrophic lateral sclerosis
Creators: Yuping Song - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Monica Castanedes-Casey - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Linda Rousseau - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Virginia Phillips - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Dennis W Dickson - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Rosa Rademakers - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
John D Fryer - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Beth K Rush - Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA
Otto Pedraza - Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA
Ana M Caputo - Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Pamela Desaro - Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Carla Palmucci - Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Amelia Robertson - Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Michael G Heckman - Section of Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA
Nancy N Diehl - Section of Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA
Edythe Wiggs - Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Michael Tierney - Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Laura Braun - Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Jennifer Farren - Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
David Lacomis - Departments of Neurology and Pathology, University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
Shafeeq Ladha - Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA
Christina N Fournier - Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
Leo F McCluskey - Department of Neurology and the Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA
Lauren B Elman - Department of Neurology and the Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA
Jon B Toledo - Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Jennifer D McBride - Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Cinzia Tiloca - Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
Claudia Morelli - Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
Barbara Poletti - Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
Federica Solca - Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
Alessandro Prelle - Department of Neurology and Stroke Unit, Ospedale Maggiore di Crema, Crema, Italy
Joanne Wuu - Department of Neurology, University of Miami, Miami, FL 33136, USA
Jennifer Jockel-Balsarotti - Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
Frank Rigo - Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA
Christine Ambrose - Aleta Biotherapeutics, Natick, MA 01760, USA
Abhishek Datta - Protein Chemistry, Biogen Idec, Cambridge, MA 02142, USA
Weixing Yang - Protein Chemistry, Biogen Idec, Cambridge, MA 02142, USA
Denitza Raitcheva - Global Biomarker and Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA
Giovanna Antognetti - Biologics Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA
Alexander McCampbell - Neurology Research, Biogen Idec, Cambridge, MA 02142, USA
John C Van Swieten - Department of Neurology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands
Tania F Gendron - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Bruce L Miller - Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA
Jeannie Chew - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Adam L Boxer - Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA
Jeannette N Stankowski - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Robert H Brown - Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
Lindsey R Hayes - Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA
Robert Bowser - Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA
Timothy M Miller - Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
Yong-Jie Zhang - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Mercedes Prudencio - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
John Q Trojanowski - Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Yari Carlomagno - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Murray Grossman - Department of Neurology and the Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA
James D Berry - Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA 02114, USA
Lillian M Daughrity - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Karen Jansen-West - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
William T Hu - Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA
Antonia Ratti - Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy
Emilie A Perkerson - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Aliesha O'Raw - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Bryan J Traynor - Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA
Casey Cook - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Matthew D Disney - Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA
Luc Pregent - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Michael Benatar - Department of Neurology, University of Miami, Miami, FL 33136, USA
Veronique Belzil - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Vincenzo Silani - Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy
Marka van Blitterswijk - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Jonathan D Glass - Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA
Lilia J Tabassian - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Mary Kay Floeter - Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
Chris W Lee - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Jeffrey D Rothstein - Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA
Mei Yue - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Kevin B Boylan - Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Jimei Tong - Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
Leonard Petrucelli - Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA
Publication Details: Science translational medicine, Vol.9(383), pp.eaai7866-eaai7866
Publisher: United States
Grant note: Z01 AG000949 / Intramural NIH HHS U54 NS092091 / NINDS NIH HHS P30 AG010124 / NIA NIH HHS U54 NS092089 / NINDS NIH HHS P01 AG017586 / NIA NIH HHS R01 NS085207 / NINDS NIH HHS DP1 NS096898 / NINDS NIH HHS P01 NS084974 / NINDS NIH HHS R21 NS084528 / NINDS NIH HHS U54 NS091046 / NINDS NIH HHS R21 NS089979 / NINDS NIH HHS R01 NS088689 / NINDS NIH HHS K23 AG042856 / NIA NIH HHS R35 NS097273 / NINDS NIH HHS R01 NS078398 / NINDS NIH HHS R25 NS065729 / NINDS NIH HHS
Academic Unit: UMMG Dept of Neurology - Neuromuscular Disorders Div; Miller School of Medicine; UMMG Department of Neurology
Language: English
Resource Type: Journal article
PMID: 28356511
PMCID: PMC5576451
Record Identifier: 991031576266902976