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

Authors

Sara Saez-Atienzar, Cleide Dos Santos Souza, Ruth Chia, Selina N Beal, Ileana Lorenzini, Ruili Huang, Jennifer Levy, Camelia Burciu, Jinhui Ding, J Raphael Gibbs, Ashley Jones, Ramita Dewan, Viviana Pensato, Silvia Peverelli, Lucia Corrado, Joke J F A van Vugt, Wouter van Rheenen, Ceren Tunca, Elif Bayraktar, Menghang Xia, International ALS Genomics Consortium, ITALSGEN Consortium, SLAGEN Consortium, Project MinE ALS Sequencing Consortium, Alfredo Iacoangeli, Aleksey Shatunov, Cinzia Tiloca, Nicola Ticozzi, Federico Verde, Letizia Mazzini, Kevin Kenna, Ahmad Al Khleifat, Sarah Opie-Martin, Flavia Raggi, Massimiliano Filosto, Stefano Cotti Piccinelli, Alessandro Padovani, Stella Gagliardi, Maurizio Inghilleri, Alessandra Ferlini, Rosario Vasta, Andrea Calvo, Cristina Moglia, Antonio Canosa, Umberto Manera, Maurizio Grassano, Jessica Mandrioli, Gabriele Mora, Christian Lunetta, Raffaella Tanel, Francesca Trojsi, Patrizio Cardinali, Salvatore Gallone, Maura Brunetti, Daniela Galimberti, Maria Serpente, Chiara Fenoglio, Elio Scarpini, Giacomo P Comi, Stefania Corti, Roberto Del Bo, Mauro Ceroni, Giuseppe Lauria Pinter, Franco Taroni, Eleonora Dalla Bella, Enrica Bersano, Charles J Curtis, Sang Hyuck Lee, Raymond Chung, Hamel Patel, Karen E Morrison, Johnathan Cooper-Knock, Pamela J Shaw, Gerome Breen, Richard J B Dobson, Clifton L Dalgard, American Genome Center, Sonja W Scholz, Ammar Al-Chalabi, Leonard H van den Berg, Russell McLaughlin, Orla Hardiman, Cristina Cereda, Gianni Sorarù, Sandra D'Alfonso, Siddharthan Chandran, Suvankar Pal, Antonia Ratti, Cinzia Gellera, Kory Johnson, Tara Doucet-O'Hare, Nicholas Pasternack, Tongguang Wang, Avindra Nath, Gabriele Siciliano, Vincenzo Silani, Ayşe Nazlı Başak, Jan H Veldink, William Camu, Jonathan D Glass, John E Landers, Adriano Chiò, Rita Sattler, Christopher E Shaw, Laura Ferraiuolo, Isabella Fogh, Bryan J Traynor

Abstract

Cell Genom. 2024 Oct 19:100679. doi: 10.1016/j.xgen.2024.100679. Online ahead of print.

ABSTRACT

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.

PMID:39437787 | DOI:10.1016/j.xgen.2024.100679