Therapeutic targeting of ALS pathways: refocusing an incomplete picture

Detalhes bibliográficos
Autor(a) principal: Maragakis, Nicholas J.
Data de Publicação: 2023
Outros Autores: Carvalho, Mamede, Weiss, Michael D.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/59916
Resumo: © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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spelling Therapeutic targeting of ALS pathways: refocusing an incomplete picture© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Numerous potential amyotrophic lateral sclerosis (ALS)-relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS-relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well-established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.Research funding: Cytokinetics National Institutes of Health, USA. Grant Number: 5R01NS117604-03WileyRepositório da Universidade de LisboaMaragakis, Nicholas J.Carvalho, MamedeWeiss, Michael D.2023-10-20T14:07:44Z20232023-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/59916engAnn Clin Transl Neurol. 2023 Aug 2810.1002/acn3.518872328-9503info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:09:19Zoai:repositorio.ul.pt:10451/59916Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:09:43.783561Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Therapeutic targeting of ALS pathways: refocusing an incomplete picture
title Therapeutic targeting of ALS pathways: refocusing an incomplete picture
spellingShingle Therapeutic targeting of ALS pathways: refocusing an incomplete picture
Maragakis, Nicholas J.
title_short Therapeutic targeting of ALS pathways: refocusing an incomplete picture
title_full Therapeutic targeting of ALS pathways: refocusing an incomplete picture
title_fullStr Therapeutic targeting of ALS pathways: refocusing an incomplete picture
title_full_unstemmed Therapeutic targeting of ALS pathways: refocusing an incomplete picture
title_sort Therapeutic targeting of ALS pathways: refocusing an incomplete picture
author Maragakis, Nicholas J.
author_facet Maragakis, Nicholas J.
Carvalho, Mamede
Weiss, Michael D.
author_role author
author2 Carvalho, Mamede
Weiss, Michael D.
author2_role author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Maragakis, Nicholas J.
Carvalho, Mamede
Weiss, Michael D.
description © 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
publishDate 2023
dc.date.none.fl_str_mv 2023-10-20T14:07:44Z
2023
2023-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/59916
url http://hdl.handle.net/10451/59916
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Ann Clin Transl Neurol. 2023 Aug 28
10.1002/acn3.51887
2328-9503
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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