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Author Notes:

Corresponding author. Email: petrucelli.leonard@mayo.edu

See publication for full list of author contributions.

We thank all patients who donated samples and the NIH centers and programs that made this possible.

We thank T. Hyman for sample processing at the Washington University and C. Henderson for insight on our study.

All requests for reagents (that is, antibodies and adeno-associated virus) should be made to L. Petrucelli.

They will be made available through appropriate administrative channels (material transfer agreements).

See publication for full list of disclosures.


Research Funding:

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.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • ALS

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

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Journal Title:

Science Translational Medicine


Volume 9, Number 383


, Pages eaai7866-eaai7866

Type of Work:

Article | Post-print: After Peer Review


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. 2017

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