期刊
JCI INSIGHT
卷 2, 期 22, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.97152
关键词
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资金
- Canadian Institutes of Health Research (CIHR)
- Reseau Medical de Genetique Appliquee fellowships
- CIHR fellowship
- Canada Research Chairs
- Genome Quebec
- Frick Foundation for ALS Research
- US Department of Defense CDMRP/ALSRP
- Brain Canada
- OCE-CQDM
- Weston Brain Institute
- Muscular Dystrophy Association USA
- CIHR
- ALS Association
- NIH [R00NS077435, R01NS097850]
- Hotchkiss Brain Institute
- Clinical Research Unit at the University of Calgary
- South Health Campus, Calgary, Alberta
- FRQS Research Scholar Award
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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