Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.
Saez-Atienzar Sara, Souza Cleide Dos Santos, Chia Ruth, Beal Selina N, Lorenzini Ileana, Huang Ruili, Levy Jennifer, Burciu Camelia, Ding Jinhui, Gibbs J Raphael, Jones Ashley, Dewan Ramita, Pensato Viviana, Peverelli Silvia, Corrado Lucia, van Vugt Joke J F A, van Rheenen Wouter, Tunca Ceren, Bayraktar Elif, Xia Menghang, International ALS Genomics Consortium, ITALSGEN Consortium, SLAGEN Consortium, Project MinE ALS Sequencing Consortium, Iacoangeli Alfredo, Shatunov Aleksey, Tiloca Cinzia, Ticozzi Nicola, Verde Federico, Mazzini Letizia, Kenna Kevin, Al Khleifat Ahmad, Opie-Martin Sarah, Raggi Flavia, Filosto Massimiliano, Piccinelli Stefano Cotti, Padovani Alessandro, Gagliardi Stella, Inghilleri Maurizio, Ferlini Alessandra, Vasta Rosario, Calvo Andrea, Moglia Cristina, Canosa Antonio, Manera Umberto, Grassano Maurizio, Mandrioli Jessica, Mora Gabriele, Lunetta Christian, Tanel Raffaella, Trojsi Francesca, Cardinali Patrizio, Gallone Salvatore, Brunetti Maura, Galimberti Daniela, Serpente Maria, Fenoglio Chiara, Scarpini Elio, Comi Giacomo P, Corti Stefania, Del Bo Roberto, Ceroni Mauro, Pinter Giuseppe Lauria, Taroni Franco, Bella Eleonora Dalla, Bersano Enrica, Curtis Charles J, Lee Sang Hyuck, Chung Raymond, Patel Hamel, Morrison Karen E, Cooper-Knock Johnathan, Shaw Pamela J, Breen Gerome, Dobson Richard J B, Dalgard Clifton L, American Genome Center, Scholz Sonja W, Al-Chalabi Ammar, van den Berg Leonard H, McLaughlin Russell, Hardiman Orla, Cereda Cristina, Sorarù Gianni, D'Alfonso Sandra, Chandran Siddharthan, Pal Suvankar, Ratti Antonia, Gellera Cinzia, Johnson Kory, Doucet-O'Hare Tara, Pasternack Nicholas, Wang Tongguang, Nath Avindra, Siciliano Gabriele, Silani Vincenzo, Başak Ayşe Nazlı, Veldink Jan H, Camu William, Glass Jonathan D, Landers John E, Chiò Adriano, Sattler Rita, Shaw Christopher E, Ferraiuolo Laura, Fogh Isabella, Traynor Bryan J
СтатьяResearch Support, N.I.H., IntramuralПоддержка правительства СШАПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаПеревод в очереди
Аннотация
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.
Для цитирования: Saez-Atienzar Sara, Souza Cleide Dos Santos, Chia Ruth, Beal Selina N, Lorenzini Ileana, Huang Ruili, Levy Jennifer, Burciu Camelia, Ding Jinhui, Gibbs J Raphael, Jones Ashley, Dewan Ramita, Pensato Viviana, Peverelli Silvia, Corrado Lucia, van Vugt Joke J F A, van Rheenen Wouter, Tunca Ceren, Bayraktar Elif, Xia Menghang, International ALS Genomics Consortium, ITALSGEN Consortium, SLAGEN Consortium, Project MinE ALS Sequencing Consortium, Iacoangeli Alfredo, Shatunov Aleksey, Tiloca Cinzia, Ticozzi Nicola, Verde Federico, Mazzini Letizia, Kenna Kevin, Al Khleifat Ahmad, Opie-Martin Sarah, Raggi Flavia, Filosto Massimiliano, Piccinelli Stefano Cotti, Padovani Alessandro, Gagliardi Stella, Inghilleri Maurizio, Ferlini Alessandra, Vasta Rosario, Calvo Andrea, Moglia Cristina, Canosa Antonio, Manera Umberto, Grassano Maurizio, Mandrioli Jessica, Mora Gabriele, Lunetta Christian, Tanel Raffaella, Trojsi Francesca, Cardinali Patrizio, Gallone Salvatore, Brunetti Maura, Galimberti Daniela, Serpente Maria, Fenoglio Chiara, Scarpini Elio, Comi Giacomo P, Corti Stefania, Del Bo Roberto, Ceroni Mauro, Pinter Giuseppe Lauria, Taroni Franco, Bella Eleonora Dalla, Bersano Enrica, Curtis Charles J, Lee Sang Hyuck, Chung Raymond, Patel Hamel, Morrison Karen E, Cooper-Knock Johnathan, Shaw Pamela J, Breen Gerome, Dobson Richard J B, Dalgard Clifton L, American Genome Center, Scholz Sonja W, Al-Chalabi Ammar, van den Berg Leonard H, McLaughlin Russell, Hardiman Orla, Cereda Cristina, Sorarù Gianni, D'Alfonso Sandra, Chandran Siddharthan, Pal Suvankar, Ratti Antonia, Gellera Cinzia, Johnson Kory, Doucet-O'Hare Tara, Pasternack Nicholas, Wang Tongguang, Nath Avindra, Siciliano Gabriele, Silani Vincenzo, Başak Ayşe Nazlı, Veldink Jan H, Camu William, Glass Jonathan D, Landers John E, Chiò Adriano, Sattler Rita, Shaw Christopher E, Ferraiuolo Laura, Fogh Isabella, Traynor Bryan J. Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data.. Cell genomics. 2024. DOI: 10.1016/j.xgen.2024.100679.
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