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Sci Transl Med. 2017 Mar 29;9(383). pii: eaai7866. doi: 10.1126/scitranslmed.aai7866.

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

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
2
Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA.
3
Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
4
Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA.
5
Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
6
Section of Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA.
7
Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
8
Departments of Neurology and Pathology, University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
9
Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
10
Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
11
Department of Neurology and the Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
12
Department of Neurology, Houston Methodist Neurological Institute, Houston, TX 77030, USA.
13
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
14
Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
15
Department of Neurology and Stroke Unit, Ospedale Maggiore di Crema, Crema, Italy.
16
Department of Neurology, University of Miami, Miami, FL 33136, USA.
17
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
18
Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
19
Aleta Biotherapeutics, Natick, MA 01760, USA.
20
Protein Chemistry, Biogen Idec, Cambridge, MA 02142, USA.
21
Global Biomarker and Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA.
22
Biologics Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA.
23
Neurology Research, Biogen Idec, Cambridge, MA 02142, USA.
24
Department of Neurology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands.
25
Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
26
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
27
Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA 02114, USA.
28
Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy.
29
Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA.
30
Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
31
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
32
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. petrucelli.leonard@mayo.edu.

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.

PMID:
28356511
PMCID:
PMC5576451
DOI:
10.1126/scitranslmed.aai7866
[Indexed for MEDLINE]
Free PMC Article

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