Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

Shunmoogum A. Patten; Dina Aggad; Jose Martinez; Elsa Tremblay; Janet Petrillo; Gary A.B. Armstrong; Alexandre La Fontaine; Claudia Maios; Meijiang Liao; Sorana Ciura; Xiao Yan Wen; Victor Rafuse; Justin Ichida; Lorne Zinman; Jean Pierre Julien; Edor Kabashi; Richard Robitaille; Lawrence Korngut; J. Alexander Parker; Pierre Drapeau

doi:10.1172/jci.insight.97152

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

Shunmoogum A. Patten, Dina Aggad, Jose Martinez, Elsa Tremblay, Janet Petrillo, Gary A.B. Armstrong, Alexandre La Fontaine, Claudia Maios, Meijiang Liao, Sorana Ciura, Xiao Yan Wen, Victor Rafuse, Justin Ichida, Lorne Zinman, Jean Pierre Julien, Edor Kabashi, Richard Robitaille, Lawrence Korngut, J. Alexander Parker, Pierre Drapeau

Medicine

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

77 Citas (Scopus)

Resumen

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca²⁺ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

Idioma original	English
Número de artículo	e97152
Publicación	JCI insight
Volumen	2
N.º	22
DOI	https://doi.org/10.1172/jci.insight.97152
Estado	Published - nov. 16 2017

Nota bibliográfica

Funding Information:
We express our heartfelt thanks to the patients who participated in this study. The authors would also like to thank Marina Drits and Guy Laliberté for excellent care of the zebrafish. We thank Guy Rouleau for introducing many of us to ALS research and for providing the TARDBP, FUS, and SOD1 clones used; Randall Peterson for guiding us in the design of the chemical genetic screens; and Terry Snutch for insights to pimozide pharmacology. SAP was supported by Canadian Institutes of Health Research (CIHR) and the Réseau Médical de Génétique Appliquée fellowships. GABA was supported by a CIHR fellowship. PD and JPJ were supported by Canada Research Chairs, and JKI is a New York Stem Cell Foundation Robertson Investigator. The biological studies were supported by Genome Québec (PD and EK), the Frick Foundation for ALS Research (PD, AP), the US Department of Defense CDMRP/ALSRP (PD, JAP, EK and JPJ), Brain Canada and OCE-CQDM (PD and X-YW), the Weston Brain Institute (PD, GABA, RR), the Muscular Dystrophy Association USA (JAP), the CIHR (JAP, PD, RR), the ALS Association (PD, AP, X-YW, RR), and NIH grants R00NS077435 and R01NS097850 (JKI). The clinical study was funded through a generous donation from the Quirk family (Calgary, Alberta, Canada) and a grant from the Hotchkiss Brain Institute and the Clinical Research Unit at the University of Calgary. Patient study visit space and support was provided by South Health Campus, Calgary, Alberta. Statistical analysis support was provided by the Clinical Research Unit, Faculty of Medicine, University of Calgary. SAP was supported by Canadian Institutes of Health Research (CIHR) and the Réseau Médical de Génétique Appli-quée fellowships. GABA was supported by a CIHR fellowship. JAP was supported by a FRQS Research Scholar Award, PD and JPJ were supported by Canada Research Chairs, and JKI is a New York Stem Cell Foundation Robertson Investigator.

Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.

ASJC Scopus Subject Areas

General Medicine

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Patten, S. A., Aggad, D., Martinez, J., Tremblay, E., Petrillo, J., Armstrong, G. A. B., Fontaine, A. L., Maios, C., Liao, M., Ciura, S., Wen, X. Y., Rafuse, V., Ichida, J., Zinman, L., Julien, J. P., Kabashi, E., Robitaille, R., Korngut, L., Parker, J. A., & Drapeau, P. (2017). Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis. JCI insight, 2(22), Artículo e97152. https://doi.org/10.1172/jci.insight.97152

Patten, SA, Aggad, D, Martinez, J, Tremblay, E, Petrillo, J, Armstrong, GAB, Fontaine, AL, Maios, C, Liao, M, Ciura, S, Wen, XY, Rafuse, V, Ichida, J, Zinman, L, Julien, JP, Kabashi, E, Robitaille, R, Korngut, L, Parker, JA & Drapeau, P 2017, 'Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis', JCI insight, vol. 2, n.º 22, e97152. https://doi.org/10.1172/jci.insight.97152

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title = "Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis",

abstract = "Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.",

author = "Patten, {Shunmoogum A.} and Dina Aggad and Jose Martinez and Elsa Tremblay and Janet Petrillo and Armstrong, {Gary A.B.} and Fontaine, {Alexandre La} and Claudia Maios and Meijiang Liao and Sorana Ciura and Wen, {Xiao Yan} and Victor Rafuse and Justin Ichida and Lorne Zinman and Julien, {Jean Pierre} and Edor Kabashi and Richard Robitaille and Lawrence Korngut and Parker, {J. Alexander} and Pierre Drapeau",

note = "Funding Information: We express our heartfelt thanks to the patients who participated in this study. The authors would also like to thank Marina Drits and Guy Lalibert{\'e} for excellent care of the zebrafish. We thank Guy Rouleau for introducing many of us to ALS research and for providing the TARDBP, FUS, and SOD1 clones used; Randall Peterson for guiding us in the design of the chemical genetic screens; and Terry Snutch for insights to pimozide pharmacology. SAP was supported by Canadian Institutes of Health Research (CIHR) and the R{\'e}seau M{\'e}dical de G{\'e}n{\'e}tique Appliqu{\'e}e fellowships. GABA was supported by a CIHR fellowship. PD and JPJ were supported by Canada Research Chairs, and JKI is a New York Stem Cell Foundation Robertson Investigator. The biological studies were supported by Genome Qu{\'e}bec (PD and EK), the Frick Foundation for ALS Research (PD, AP), the US Department of Defense CDMRP/ALSRP (PD, JAP, EK and JPJ), Brain Canada and OCE-CQDM (PD and X-YW), the Weston Brain Institute (PD, GABA, RR), the Muscular Dystrophy Association USA (JAP), the CIHR (JAP, PD, RR), the ALS Association (PD, AP, X-YW, RR), and NIH grants R00NS077435 and R01NS097850 (JKI). The clinical study was funded through a generous donation from the Quirk family (Calgary, Alberta, Canada) and a grant from the Hotchkiss Brain Institute and the Clinical Research Unit at the University of Calgary. Patient study visit space and support was provided by South Health Campus, Calgary, Alberta. Statistical analysis support was provided by the Clinical Research Unit, Faculty of Medicine, University of Calgary. SAP was supported by Canadian Institutes of Health Research (CIHR) and the R{\'e}seau M{\'e}dical de G{\'e}n{\'e}tique Appli-qu{\'e}e fellowships. GABA was supported by a CIHR fellowship. JAP was supported by a FRQS Research Scholar Award, PD and JPJ were supported by Canada Research Chairs, and JKI is a New York Stem Cell Foundation Robertson Investigator. Publisher Copyright: {\textcopyright} 2017 American Society for Clinical Investigation. All rights reserved.",

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AU - Patten, Shunmoogum A.

AU - Aggad, Dina

AU - Martinez, Jose

AU - Tremblay, Elsa

AU - Petrillo, Janet

AU - Armstrong, Gary A.B.

AU - Fontaine, Alexandre La

AU - Maios, Claudia

AU - Liao, Meijiang

AU - Ciura, Sorana

AU - Wen, Xiao Yan

AU - Rafuse, Victor

AU - Ichida, Justin

AU - Zinman, Lorne

AU - Julien, Jean Pierre

AU - Kabashi, Edor

AU - Robitaille, Richard

AU - Korngut, Lawrence

AU - Parker, J. Alexander

AU - Drapeau, Pierre

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N2 - Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

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Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

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