Poly(Gp) Proteins Are A Useful Pharmacodynamic Marker For C9Orf72-Associated Amyotrophic Lateral Sclerosis

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 Corresponding author. petrucelli.leonard@mayo.edu. *These authors contributed equally to this work. Competing interests: Anti-GP antibodies generated by T.F. G. and L. Petrucelli that were used in this study have been licensed to commercial entities. T.F. G. and L. Petrucelli have a U.S. patent #9,448,232 entitled “Methods and materials for detecting C9ORF72 hexanucleotide repeat expansion positive frontotemporal lobar degeneration or C9ORF72 hexanucleotide repeat expansion positive amyotrophic lateral sclerosis. ” A.L.B. is an advisory board member for Biogen and Ionis Pharmaceuticals, is a paid consultant for Ionis Pharmaceuticals, and collaborated with and received research funding from Biogen. A.M. has restricted stock units in Biogen, is a full-time employee of the company, and shared antibodies for this study. B.L.M. is the director of an NIH-sponsored Alzheimer’s Disease Research Center; receives support from University of California, San Francisco/Quest Diagnostics; is the scientific director of the Tau Consortium, the Consortium for Frontotemporal Dementia Research, and the John Douglas French Foundation; is a medical adviser for the Larry L. Hillblom Foundation; and is a scientific advisory board member for the Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia. B.J.T. has a paid consulting relationship with the Brain Science Institute, Department of Neurology, Johns Hopkins; receives intramural funding from the NIH (Z01-AG000949); and has a patent EP #2751284 B1 entitled “Method for diagnosing a neurodegenerative disease. ” C.A. holds shares in Biogen stock. F.R. is a paid employee of Ionis Pharmaceuticals and provided ASOs for the study. J.D. B. is an unpaid adviser to ALS One (a Massachusetts ALS nonprofit organization), an unpaid member of the executive committee for the Northeast ALS Consortium, and an unpaid expert panel member of the U.S. National ALS Registry; has been a paid consultant to Neuraltus Pharmaceuticals and Biogen; and holds the Massachusetts General Hospital–Voyager Therapeutics academic-industry fellow position (a research collaboration paid through appointment at Massachusetts General Hospital). M.G. is a governing board member of the International Society for Frontotemporal Dementia and is on the medical advisory board of the Association for Frontotemporal Dementias. M.K. F. has a paid consulting relationship with Department of Neurology, Uniformed Services University of Health Sciences as an adjunct associate professor. R.B. is the president of and holds stock options in Iron Horse Diagnostics Inc. R.H. B. is affiliated with the Angel Fund for ALS Research. S.L. has a paid consulting relationship with Barrow Neurological Institute and is an associate professor of Neurology in the University of Arizona College of Medicine, the Creighton University Medical School, and Sanofi Genzyme, for unrelated disorders. T.M. M. is a paid consultant for Cytokinetics and receives research support from Ionis Pharmaceuticals and Biogen Idec. V.S. serves on the board of Cytokinetics for the VITALITY trial in ALS and has received consultation fees. All other authors declare that they have no competing interests. SUPPLEMENTARY MATERIALS www.sciencetranslationalmedicine. org/cgi/content/full/9/383/eaai7866/DC1 Materials and Methods Author contributions: L. Petrucelli, K.B. B. , J.D.R. , T.F. G. , J.C. , J.N. S. , L.R.H. , and Y. -J.Z. contributed to the conception and design of the study. T.F. G. , M.P., L.M.D., L. Pregent, V.B. , M.v. B. , Y.S. , R.R. , B.K. R. , O.P., A.M.C. , P.D. , C.P., A. Robertson, E.W. , M.T. , L.B. , J.F. , D.L. , S.L. , C.N. F. , L.F. M. , L.B. E. , J.B. T. , J.D. M. , C.T. , C.M. , B.P., F.S. , A.P., J.W. , J.J.-B. , J.C. V.S. , B.L.M. , A.L.B. , R.H. B. , R.B. , T.M. M. , J.Q. T. , M.G. , J.D. B. , W.T. H. , A. Ratti, B.J.T. , M.B. , V.S. , J.D. G. , M.K. F. , J.D.R. , K.B. B. , and L. Petrucelli contributed to the clinical studies through the collection and processing of patient samples, provided clinical data, and provided insight. All statistical analyses for clinical studies were carried out by M.G. H. and N.N. D. Studies on lymphoblastoid cell lines were conducted by Y. -J.Z. , M.P., T.F. G. , A.O. , L.M.D., L. Pregent, and V.B. L.R.H. , T.F. G. , L.M.D., M.v. B. , R.R. , and F.R. contributed to the iPSN studies. J.C. , J.N. S. , T.F. G. , K.J.-W. , E.A.P., L.M.D., C.W. L. , L.J.T. , M.Y. , J.T. , M.C. -C. , L.R. , V.P., D.W. D. , and J.D. F. contributed to the in vivo studies. Statistical analyses related to the preclinical models were carried out by T.F. G. , J.C. , J.N. S. , L.R.H. , and Y. -J.Z. Assay validation was made possible through the efforts of T.F. G. , C.C. , Y.C. , C.A. , A.D., W.Y. , D.R. , G.A. , A.M., and M.D.D. The manuscript was written by T.F. G. , and all authors read it and provided comments and revisions. Data and materials availability: 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). HHS Public Access Author manuscript Sci Transl Med. Author manuscript; available in PMC 2018 March 29. Published in final edited form as: Sci Transl Med. 2017 March 29; 9(383): . doi:10.1126/scitranslmed.aai7866. A uhor M anscript