Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 383, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aai7866
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Funding
- NIH/National Institute on Aging [P01AG017586, K23AG042856, AG10124]
- NIH/National Institute of Neurological Disorders and Stroke [R21NS089979, R25NS065729, R01NS078398, R35NS097273, R21NS084528, P01NS084974, R01NS088689, R01NS085207, U54NS091046]
- intramural research program of the NIH/National Institute of Neurological Disorders and Stroke [Z01NS003146]
- U.S. Department of Defense (Amyotrophic Lateral Sclerosis Research Program) [AL130125]
- Mayo Clinic Foundation
- Mayo Clinic Center for Individualized Medicine
- Amyotrophic Lateral Sclerosis Association
- Robert Packard Center for ALS Research at Johns Hopkins
- Target ALS
- Association for Frontotemporal Degeneration
- Biogen
- ALS Therapy Alliance
- ALS Finding A Cure Foundation
- Brain Science Institute
- Muscular Dystrophy Association [416137, 4365, 172123]
- Italian Ministry of Health [RF-2013-02355764]
- STRENGTH project - EU Joint Programme-Neurodegenerative Disease Research
- Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) [U54-NS-092091]
- Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) [U54-NS-092089]
- NCATS
- National Institute of Neurological Disorders and Stroke
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There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G(4)C(2) 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. G(4)C(2) 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 G(4)C(2) 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(4)C(2) 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 G(4)C(2) RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G(4)C(2) RNA and downstream G(4)C(2) RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G(4)C(2) RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.
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