Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.

TitleNeuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis.
Publication TypeJournal Article
Year of Publication2017
AuteursPatten, SA, Aggad, D, Martinez, J, Tremblay, E, Petrillo, J, Armstrong, GAb, La Fontaine, A, Maios, C, Liao, M, Ciura, S, Wen, X-Y, Rafuse, V, Ichida, J, Zinman, L, Julien, J-P, Kabashi, E, Robitaille, R, Korngut, L, J Parker, A, Drapeau, P
JournalJCI Insight
Volume2
Issue22
Date Published2017 Nov 16
ISSN2379-3708
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.

DOI10.1172/jci.insight.97152
Alternate JournalJCI Insight
PubMed ID29202456
PubMed Central IDPMC5752378
Grant ListR00 NS077435 / NS / NINDS NIH HHS / United States
R01 NS097850 / NS / NINDS NIH HHS / United States