Article
作者: Laaksovirta, Hannu ; Ticozzi, Nicola ; Cereda, Cristina ; Beal, Selina N ; Breen, Gerome ; Shaw, Christopher E ; Curtis, Charles J ; Spataro, Rossella ; Silani, Vincenzo ; Trojsi, Francesca ; Fenoglio, Chiara ; Raggi, Flavia ; Heiman-Patterson, Terry D. ; Grassano, Maurizio ; Gibson, Summer B. ; Kirby, Janine ; Ostrow, Lyle W. ; Jones, Ashley ; Floeter, Mary Kay ; Verde, Federico ; Mandrioli, Jessica ; Taroni, Franco ; Ferraiuolo, Laura ; Doucet-O’Hare, Tara ; Sattler, Rita ; Martinelli, Ilaria ; Salivetto, Marco ; de Carvalho, Mamede ; Ceroni, Mauro ; Chandran, Siddharthan ; Broach, James ; Weber, Markus ; Chiò, Adriano ; Nath, Avindra ; Veldink, Jan H ; Trojsi, Francesca ; Brice, Alexis ; Al-Chalabi, Ammar ; Kenna, Kevin ; Tiloca, Cinzia ; Carrera, Paola ; Chung, Raymond ; Drory, Vivian ; Salvi, Erika ; Shaw, Chris ; Mazzini, Letizia ; Pinter, Giuseppe Lauria ; Sorarù, Gianni ; Passaniti, Carla ; Chung, Raymond ; Cardinali, Patrizio ; Ferraro, Pilar M. ; Landers, John E ; Stone, David J. ; Filosto, Massimiliano ; Chandran, Siddharthan ; Gianferrari, Giulia ; Iacoangeli, Alfredo ; Robberecht, Wim ; Vasta, Rosario ; Galimberti, Daniela ; Al Khleifat, Ahmad ; Burciu, Camelia ; Barberis, Marco ; Scholz, Sonja W ; Van Damme, Philip ; Camu, William ; Gellera, Cinzia ; Valori, Miko ; Cardinali, Patrizio ; van den Berg, Leonard H. ; Pensato, Viviana ; D'Errico, Eustachio ; Shatunov, Aleksey ; Ratti, Antonia ; Riolo, Giulia ; Iazzolino, Barbara ; Vasta, Rosario ; Mandrioli, Jessica ; Corti, Stefania ; Filippi, Massimo ; Shaw, Pamela J. ; Lee, Sang Hyuck ; MacGowan, Daniel JL. ; Serpente, Maria ; Scarpini, Elio ; Orrell, Richard W. ; La Bella, Vincenzo ; Tremolizzo, Lucio ; Wilkerson, Matthew D. ; Comi, Giacomo P. ; Brady, Christopher B. ; Rogaeva, Ekaterina ; Renton, Alan E. ; Bowser, Robert ; Başak, Ayşe Nazlı ; Inghilleri, Maurizio ; Calvo, Andrea ; Russo, Massimo ; Beal, Selina N. ; Castellotti, Barbara ; Silani, Vincenzo ; Van Deerlin, Vivianna M. ; Dobson, Richard J B ; Floris, Gianluca ; Ferrarese, Carlo ; Cooper-Knock, John ; Chia, Ruth ; Tanel, Raffaella ; Levy, Jennifer ; Pickering-Brown, Stuart ; Logullo, Francesco O. ; Traynor, Bryan J. ; Gellera, Cinzia ; Soltis, Anthony R. ; Glass, Jonathan D ; Cooper-Knock, Johnathan ; Van Den Bosch, Ludo ; Gibbs, J. Raphael ; Galimberti, Daniela ; Calvo, Andrea ; Raggi, Flavia ; Wang, Tongguang ; Andersen, Peter ; Corcia, Philippe ; Mora, Gabriele ; Hardiman, Orla ; Cereda, Cristina ; Tunca, Ceren ; Landi, Francesco ; Johnson, Kory ; Sorarù, Gianni ; Alba, Camille ; Lumbroso, Serge ; Simoncini, Costanza ; Baloh, Robert H. ; Camu, William ; Comi, Giacomo P ; Conti, Elisa ; Monsurrò, Maria Rosaria ; Corti, Stefania ; Fuda, Giuseppe ; Verde, Federico ; Sideri, Riccardo ; Başak, Ayşe Nazlı ; Myllykangas, Liisa ; Origone, Paola ; Angelocola, Stefania M. ; Veldink, Jan H. ; Troncoso, Juan C. ; Tedeschi, Gioacchino ; Gibbs, J Raphael ; Pozzi, Susanna ; Simonini, Cecilia ; Del Bo, Roberto ; Brunetti, Maura ; Grassano, Maurizio ; Dubbioso, Raffaele ; Taroni, Franco ; Johnson, Kory ; Fenoglio, Chiara ; Corbo, Massimo ; Opie-Martin, Sarah ; Morrison, Karen E. ; Tranquilli, Stefania ; van Vugt, Joke J.F.A. ; Filosto, Massimiliano ; Ferlini, Alessandra ; Sendtner, Michael ; Couratier, Philippe ; Guissart, Claire ; D’Alfonso, Sandra ; Jansson, Lilja ; Marangi, Giuseppe ; Mora, Gabriele ; van Rheenen, Wouter ; Marrosu, Maria Giovanna ; Lunetta, Christian ; Souza, Cleide dos Santos ; McLaughlin, Russell ; Chiò, Adriano ; Ceroni, Mauro ; Drepper, Carsten ; Curtis, Charles J. ; Siciliano, Gabriele ; Fratta, Pietro ; Siciliano, Gabriele ; van den Berg, Leonard H ; Ferraiuolo, Laura ; Giannini, Fabio ; Messina, Sonia ; Povedano, Monica ; Ticca, Anna ; Trojanowski, John Q. ; Al Khleifat, Ahmad ; Drory, Vivian E. ; Hupalo, Daniel N. ; Dalgard, Clifton L. ; Quattrini, Angelo ; Mazzini, Letizia ; Del Bo, Roberto ; Bacikova, Dagmar ; Volanti, Paolo ; Salvi, Fabrizio ; Moglia, Cristina ; Logroscino, Giancarlo ; Kenna, Kevin ; McGrath Martinez, Elisa ; Bersano, Enrica ; Pioro, Erik P. ; Lorenzini, Ileana ; Scarpini, Elio ; Pirisi, Angelo ; Serpente, Maria ; Ricci, Claudia ; Viollet, Coralie ; Moglia, Cristina ; Pugliatti, Maura ; Scholz, Sonja W. ; Ratti, Antonia ; Souza, Cleide Dos Santos ; Cooper-Knock, Johnathan ; Doucet-O'Hare, Tara ; Pasternack, Nicholas ; Hardiman, Orla ; Zucchi, Elisabetta ; Al-Chalabi, Ammar ; Zollino, Marcella ; Bartolomei, Ilaria ; Conte, Amelia ; Landers, John E. ; van Vugt, Joke J F A ; Gerhard, Glenn ; Vacchiano, Veria ; Petrucci, Antonio ; Sabatelli, Mario ; Iacoangeli, Alfredo ; Pinter, Giuseppe Lauria ; Fini, Nicola ; Cabona, Corrado ; Sidle, Katie C. ; Bella, Eleonora Dalla ; Torriello, Antonella ; Xia, Menghang ; Canosa, Antonio ; Simone, Isabella ; Mosca, Lorena ; Dunckley, Travis L. ; Ferlini, Alessandra ; Gotkine, Marc ; Breen, Gerome ; Lattante, Serena ; Sattler, Rita ; Introna, Alessandro ; Tiloca, Cinzia ; Dewan, Ramita ; Patel, Hamel ; Bella, Eleonora Dalla ; Sbaiz, Luca ; Tienari, Pentti J. ; Colletti, Tiziana ; Nath, Avindra ; Gallone, Salvatore ; Peverelli, Silvia ; Marinou, Kalliopi ; Wang, Tongguang ; Salamone, Paolina ; Fogh, Isabella ; Pasternack, Nicholas ; D'Alfonso, Sandra ; Glass, Jonathan D. ; Brunetti, Maura ; Battistini, Stefania ; Santarelli, Marialuisa ; Lee, Sang Hyuck ; Ravits, John M. ; Canale, Fabrizio ; Lo Gerfo, Annalisa ; Adeleye, Adelani ; Fogh, Isabella ; DeMarco, Giovanni ; Huang, Ruili ; Inghilleri, Maurizio ; Sukumar, Gauthaman ; Riva, Nilo ; Pulst, Stefan M. ; Padovani, Alessandro ; Bisogni, Giulia ; McLaughlin, Russell ; Manera, Umberto ; Ticozzi, Nicola ; Gagliardi, Stella ; Ausiello, Francesco P. ; Murru, Maria R. ; Pal, Suvankar ; Capasso, Margherita ; Manganelli, Fiore ; van den Veldink, Jan H. ; Gallone, Salvatore ; Hardy, John ; Zinman, Lorne ; Simmons, Zachary ; Shatunov, Aleksey ; Berg, Leonard H. ; Rothstein, Jeffrey D. ; Petrelli, Cristina ; Vita, Giuseppe ; Liguori, Rocco ; Greco, Lucia ; Cusi, Daniele ; Piccinelli, Stefano Cotti ; Harms, Matthew B. ; Bayraktar, Elif ; Shaw, Christopher E. ; Dalgard, Clifton L ; Gagliardi, Stella ; Bersano, Enrica ; Morrison, Karen E ; Caponnetto, Claudia ; Dobson, Richard J.B. ; Casale, Federico ; Borghero, Giuseppe ; Pal, Suvankar ; Mandich, Paola ; Feldman, Eva ; Traynor, Bryan J ; Ding, Jinhui ; Lauria, Giuseppe ; Goutman, Stephen A. ; Vourc'h, Patrick ; Piccinelli, Stefano Cotti ; Patel, Hamel ; Mouzat, Kevin ; Shaw, Pamela J ; Chio, Adriano ; Tanel, Raffaella ; Manera, Umberto ; Cuccu, Stefania ; Conforti, Francesca L. ; Lunetta, Christian ; Le Ber, Isabelle ; Cantisani, Teresa A. ; Corrado, Lucia ; Mora Pardina, Jesus S. ; Padovani, Alessandro ; Canosa, Antonio ; Maragakis, Nicholas J. ; Opie-Martin, Sarah ; Saez-Atienzar, Sara
Repeat 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.