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Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data

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dc.contributor.coauthorSaez-Atienzar S., Souza C.D.S., Chia R., Beal S.N., Lorenzini I., Huang R., Levy J., Burciu C., Ding J., Gibbs J.R., Jones A., Dewan R., Pensato V., Peverelli S., Corrado L., van Vugt J.J.F.A., van Rheenen W., Tunca C., Bayraktar E., Xia M., Baloh R.H., Bowser R., Brady C.B., Brice A., Broach J., Camu W., Chio A., Cooper-Knock J., Cusi D., Drepper C., Drory V.E., Dunckley T.L., Feldman E., Floeter M.K., Fratta P., Gerhard G., Gibson S.B., Glass J.D., Goutman S.A., Hardy J., Harms M.B., Heiman-Patterson T.D., Jansson L., Kirby J., Laaksovirta H., Landers J.E., Landi F., Le Ber I., Lumbroso S., Guissart C., MacGowan D.J., Maragakis N.J., Mora G., Mouzat K., Myllykangas L., Orrell R.W., Ostrow L.W., Pickering-Brown S., Pioro E.P., Pulst S.M., Ravits J.M., Renton A.E., Robberecht W., Rogaeva E., Rothstein J.D., Salvi E., Scholz S.W., Sendtner M., Shaw P.J., Sidle K.C., Simmons Z., Stone D.J., Tienari P.J., Traynor B.J., Trojanowski J.Q., Troncoso J.C., Valori M., Van Damme P., Van Deerlin V.M., Van Den Bosch L., Zinman L., Angelocola S.M., Ausiello F.P., Barberis M., Bartolomei I., Battistini S., Bersano E., Bisogni G., Borghero G., Brunetti M., Cabona C., Calvo A., Canale F., Canosa A., Cantisani T.A., Capasso M., Caponnetto C., Cardinali P., Carrera P., Casale F., Colletti T., Conforti F.L., Conte A., Conti E., Corbo M., Cuccu S., Bella E.D., D'Errico E., DeMarco G., Dubbioso R., Ferrarese C., Ferraro P.M., Filippi M., Fini N., Floris G., Fuda G., Gallone S., Gianferrari G., Giannini F., Grassano M., Greco L., Iazzolino B., Introna A., La Bella V., Lattante S., Lauria G., Liguori R., Logroscino G., Logullo F.O., Lunetta C., Mandich P., Mandrioli J., Manera U., Manganelli F., Marangi G., Marinou K., Marrosu M.G., Martinelli I., Messina S., Moglia C., Monsurrò M.R., Mosca L., Murru M.R., Origone P., Passaniti C., Petrelli C., Petrucci A., Pirisi A., Pozzi S., Pugliatti M., Quattrini A., Ricci C., Riolo G., Riva N., Russo M., Sabatelli M., Salamone P., Salivetto M., Salvi F., Santarelli M., Sbaiz L., Sideri R., Simone I., Simonini C., Spataro R., Tanel R., Tedeschi G., Ticca A., Torriello A., Tranquilli S., Tremolizzo L., Trojsi F., Vasta R., Vacchiano V., Vita G., Volanti P., Zollino M., Zucchi E., Silani V., Fogh I., Ticozzi N., Ratti A., Tiloca C., Gellera C., Pinter G.L., Taroni F., Castellotti B., Comi G.P., Corti S., Del Bo R., Cereda C., Ceroni M., Gagliardi S., Mazzini L., Sorarù G., Raggi F., Siciliano G., Simoncini C., Lo Gerfo A., Filosto M., Inghilleri M., Ferlini A., Corcia P., Couratier P., Vourc'h P., Hardiman O., McLaughlin R., Gotkine M., Drory V., van den Veldink J.H., Berg L.H., de Carvalho M., Mora Pardina J.S., Povedano M., Andersen P., Weber M., Başak A.N., Al-Chalabi A., Shaw C., Morrison K.E., Iacoangeli A., Shatunov A., Verde F., Kenna K., Al Khleifat A., Opie-Martin S., Piccinelli S.C., Padovani A., Galimberti D., Serpente M., Fenoglio C., Scarpini E., Curtis C.J., Lee S.H., Chung R., Patel H., Cooper-Knock J., Breen G., Dobson R.J.B., Dalgard C.L., Adeleye A., Alba C., Bacikova D., Hupalo D.N., McGrath Martinez E., Soltis A.R., Sukumar G., Viollet C., Wilkerson M.D., van den Berg L.H., D'Alfonso S., Chandran S., Pal S., Johnson K., Doucet-O'Hare T., Pasternack N., Wang T., Nath A., Veldink J.H., Chiò A., Sattler R., Shaw C.E., Ferraiuolo L., The International ALS Genomics Consortium, ITALSGEN Consortium, SLAGEN Consortium, Project MinE ALS Sequencing Consortium, The American Genome Center
dc.contributor.departmentKUTTAM (Koç University Research Center for Translational Medicine)
dc.contributor.departmentGraduate School of Health Sciences
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorBaşak, Ayşe Nazlı
dc.contributor.kuauthorBayraktar, Elif
dc.contributor.kuauthorTunca, Ceren
dc.contributor.schoolcollegeinstituteGRADUATE SCHOOL OF HEALTH SCIENCES
dc.contributor.schoolcollegeinstituteResearch Center
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2025-03-06T20:57:44Z
dc.date.issued2024
dc.description.abstractRepeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. Video abstract: © 2024
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipThis work was supported in part by the Intramural Research Program of the National Institutes of Health , the National Institute on Aging ( ZIA-AG000933 , ZIA-AG000934 ), the National Institute of Neurological Disorders and Stroke (NINDS), the National Center for Advancing Translational Sciences , and by Merck Sharp and Dohme Corp . (a subsidiary of Merck and Co., Kenilworth, NJ). B.J.T. received additional support from the Centers for Disease Control and Prevention , the Muscular Dystrophy Association, Microsoft Research , the Packard Center ALS Research at Johns Hopkins , and the ALS Association. L.F. is supported by the UK Medical Research Council ( MR/V027735/1 and MR/V000470/1 ) and the Motor Neurone Disease Association ( MND019801 ). A.N.B., C.T., and E.B. gratefully acknowledge the use of the services and facilities of the Ko\u00E7 University Research Center for Translational Medicine (KUTTAM), funded by the Presidency of Turkey, Head of Strategy and Budget . R.S. is supported by the Barrow Neurological Foundation . This work was also generated within the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD, https://ern-euro-nmd.eu ). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health. The authors would like to thank the Project MinE GWAS Consortium. This study also used genotype and clinical data from the Wellcome Trust Case Control Consortium and the HyperGenes Consortium. We thank the patients and research subjects who contributed samples for this study, Dr. Ruth Pfeiffer, Dr. Justin Kwan, the Laboratory of Neurogenetics staff, and the NINDS Neurodegeneration Clinic staff for their collegial support. The authors also acknowledge the Target ALS Human Post-mortem Tissue Core, the New York Genome Center for Genomics of Neurodegenerative Disease, the ALS Association, and the TOW Foundation. Additional acknowledgments may be found in the supplemental information.
dc.identifier.doi10.1016/j.xgen.2024.100679
dc.identifier.grantnoCenters for Disease Control and Prevention, CDC; Robert Packard Center for ALS Research, Johns Hopkins University; National Institute of Neurological Disorders and Stroke, NINDS; National Institutes of Health, NIH; Microsoft Research, MSR; Merck Sharp and Dohme United Kingdom, MSD; ALS Association, ALSA; Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi, KUTTAM; Barrow Neurological Foundation, BNF; National Center for Advancing Translational Sciences, NCATS; Tow Foundation; Muscular Dystrophy Association, MDA; National Institute on Aging, NIA: ZIA-AG000934, ZIA-AG000933; National Institute on Aging, NIA; Motor Neurone Disease Association, MNDA: MND019801; Motor Neurone Disease Association, MNDA; Medical Research Council, MRC: MR/V027735/1, MR/V000470/1; Medical Research Council, MRC
dc.identifier.issn2666-979X
dc.identifier.issue11
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85207811426
dc.identifier.urihttps://doi.org/10.1016/j.xgen.2024.100679
dc.identifier.urihttps://hdl.handle.net/20.500.14288/27294
dc.identifier.volume4
dc.identifier.wos1381332900001
dc.keywordsAcamprosate
dc.keywordsAge At onset
dc.keywordsAmyotrophic lateral sclerosis
dc.keywordsC9orf72
dc.keywordsDrug repurposing
dc.keywordsFrontotemporal dementia
dc.keywordsTranslation
dc.language.isoeng
dc.publisherCell Press
dc.relation.ispartofCell Genomics
dc.subjectMedicine
dc.titleMechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorBaşak, Ayşe Nazlı
local.contributor.kuauthorBayraktar, Elif
local.contributor.kuauthorTunca, Ceren
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit1GRADUATE SCHOOL OF HEALTH SCIENCES
local.publication.orgunit1Research Center
local.publication.orgunit2KUTTAM (Koç University Research Center for Translational Medicine)
local.publication.orgunit2School of Medicine
local.publication.orgunit2Graduate School of Health Sciences
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