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

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-10-19 DOI:10.1016/j.xgen.2024.100679

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, 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, 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

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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.

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利用大规模基因组数据，对治疗 C9orf72 相关 ALS/FTD 的药物进行无机制再利用。

C9orf72 基因的重复扩增是 ALS 和额颞叶痴呆症（FTD）最常见的遗传病因。与其他神经变性的遗传形式一样，确定这种突变导致神经元死亡的确切机制仍是一个难题，这种知识的缺乏阻碍了 C9orf72 相关疾病疗法的开发。我们采用了一种基于基因组数据（n = 41,273 ALS 和健康样本，n = 1,516 C9orf72 携带者）的不可知论方法来克服这些瓶颈。根据基因和表达模式匹配以及影响 C9orf72 携带者发病年龄的基因变异信息，我们进行了药物再利用筛选，发现γ-氨基丁酸类似物阿坎酸（acamprosate）是一种可用于携带 C9orf72 重复扩增患者的潜在再利用疗法。我们在细胞模型中验证了它的神经保护作用，其疗效与目前的标准疗法利鲁唑相当。我们的工作凸显了基因组学在潜在病理机制固有复杂的情况下重新设计药物用途的潜在价值。视频摘要。

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来源期刊

Cell genomics

CiteScore

7.10

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0.00%

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