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

Sara Saez-Atienzar; Cleide Dos Santos Souza; Ruth Chia; Selina N Beal; Ashley Jones; Joke J F A van Vugt; Wouter van Rheenen; Alfredo Iacoangeli; Aleksey Shatunov; 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; Charles J Curtis; Sang Hyuck Lee; Raymond Chung; Hamel Patel; Gerome Breen; Richard J B Dobson; Ammar Al-Chalabi; Christopher E Shaw; Isabella Fogh

doi:10.1016/j.xgen.2024.100679

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

Sara Saez-Atienzar, Cleide Dos Santos Souza, Ruth Chia, Selina N Beal, Ashley Jones, Joke J F A van Vugt, Wouter van Rheenen, Alfredo Iacoangeli, Aleksey Shatunov, Ahmad Al Khleifat, Sarah Opie-Martin, Flavia Raggi, Massimiliano Filosto, Stefano Cotti Piccinelli, Alessandro Padovani, Stella Gagliardi, Maurizio Inghilleri, Alessandra Ferlini, Rosario Vasta, Andrea CalvoCristina Moglia, Antonio Canosa, Umberto Manera, Charles J Curtis, Sang Hyuck Lee, Raymond Chung, Hamel Patel, Gerome Breen, Richard J B Dobson, Ammar Al-Chalabi, Christopher E Shaw, Isabella Fogh

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	100679
Pages (from-to)	100679
Journal	Cell genomics
Volume	4
Issue number	11
DOIs	https://doi.org/10.1016/j.xgen.2024.100679
Publication status	Published - 13 Nov 2024

Keywords

Humans
C9orf72 Protein/genetics
Amyotrophic Lateral Sclerosis/genetics
Drug Repositioning
Frontotemporal Dementia/genetics
Genomics/methods
Riluzole/therapeutic use
Male
Female
Neuroprotective Agents/therapeutic use
DNA Repeat Expansion/genetics

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10.1016/j.xgen.2024.100679

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Saez-Atienzar, S., Souza, C. D. S., Chia, R., Beal, S. N., Jones, A., van Vugt, J. J. F. A., van Rheenen, W., Iacoangeli, A., Shatunov, A., Al Khleifat, A., Opie-Martin, S., Raggi, F., Filosto, M., Piccinelli, S. C., Padovani, A., Gagliardi, S., Inghilleri, M., Ferlini, A., Vasta, R., ... Fogh, I. (2024). Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data. Cell genomics, 4(11), 100679. Article 100679. https://doi.org/10.1016/j.xgen.2024.100679

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

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.",

keywords = "Humans, C9orf72 Protein/genetics, Amyotrophic Lateral Sclerosis/genetics, Drug Repositioning, Frontotemporal Dementia/genetics, Genomics/methods, Riluzole/therapeutic use, Male, Female, Neuroprotective Agents/therapeutic use, DNA Repeat Expansion/genetics",

author = "Sara Saez-Atienzar and Souza, {Cleide Dos Santos} and Ruth Chia and Beal, {Selina N} and Ashley Jones and {van Vugt}, {Joke J F A} and {van Rheenen}, Wouter and Alfredo Iacoangeli and Aleksey Shatunov and {Al Khleifat}, Ahmad and Sarah Opie-Martin and Flavia Raggi and Massimiliano Filosto and Piccinelli, {Stefano Cotti} and Alessandro Padovani and Stella Gagliardi and Maurizio Inghilleri and Alessandra Ferlini and Rosario Vasta and Andrea Calvo and Cristina Moglia and Antonio Canosa and Umberto Manera and Curtis, {Charles J} and Lee, {Sang Hyuck} and Raymond Chung and Hamel Patel and Gerome Breen and Dobson, {Richard J B} and Ammar Al-Chalabi and Shaw, {Christopher E} and Isabella Fogh",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = nov,

day = "13",

doi = "10.1016/j.xgen.2024.100679",

language = "English",

volume = "4",

pages = "100679",

journal = "Cell genomics",

issn = "2666-979X",

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Saez-Atienzar, S, Souza, CDS, Chia, R, Beal, SN, Jones, A, van Vugt, JJFA, van Rheenen, W, Iacoangeli, A , Shatunov, A , Al Khleifat, A, Opie-Martin, S, Raggi, F, Filosto, M, Piccinelli, SC, Padovani, A, Gagliardi, S, Inghilleri, M, Ferlini, A, Vasta, R, Calvo, A, Moglia, C, Canosa, A, Manera, U, Curtis, CJ , Lee, SH , Chung, R , Patel, H , Breen, G , Dobson, RJB , Al-Chalabi, A , Shaw, CE & Fogh, I 2024, 'Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data', Cell genomics, vol. 4, no. 11, 100679, pp. 100679. https://doi.org/10.1016/j.xgen.2024.100679

TY - JOUR

T1 - Mechanism-free repurposing of drugs for C9orf72-related ALS/FTD using large-scale genomic data

AU - Saez-Atienzar, Sara

AU - Souza, Cleide Dos Santos

AU - Chia, Ruth

AU - Beal, Selina N

AU - Jones, Ashley

AU - van Vugt, Joke J F A

AU - van Rheenen, Wouter

AU - Iacoangeli, Alfredo

AU - Shatunov, Aleksey

AU - Al Khleifat, Ahmad

AU - Opie-Martin, Sarah

AU - Raggi, Flavia

AU - Filosto, Massimiliano

AU - Piccinelli, Stefano Cotti

AU - Padovani, Alessandro

AU - Gagliardi, Stella

AU - Inghilleri, Maurizio

AU - Ferlini, Alessandra

AU - Vasta, Rosario

AU - Calvo, Andrea

AU - Moglia, Cristina

AU - Canosa, Antonio

AU - Manera, Umberto

AU - Curtis, Charles J

AU - Lee, Sang Hyuck

AU - Chung, Raymond

AU - Patel, Hamel

AU - Breen, Gerome

AU - Dobson, Richard J B

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E

AU - Fogh, Isabella

PY - 2024/11/13

Y1 - 2024/11/13

N2 - 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.

AB - 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.

KW - Humans

KW - C9orf72 Protein/genetics

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Drug Repositioning

KW - Frontotemporal Dementia/genetics

KW - Genomics/methods

KW - Riluzole/therapeutic use

KW - Male

KW - Female

KW - Neuroprotective Agents/therapeutic use

KW - DNA Repeat Expansion/genetics

UR - http://www.scopus.com/inward/record.url?scp=85207811426&partnerID=8YFLogxK

U2 - 10.1016/j.xgen.2024.100679

DO - 10.1016/j.xgen.2024.100679

M3 - Article

C2 - 39437787

SN - 2666-979X

VL - 4

SP - 100679

JO - Cell genomics

JF - Cell genomics

IS - 11

M1 - 100679

ER -

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

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Keywords

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