A specific inhibitor of janus kinase-3 increases survival in a transgenic mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder involving the motor neurons of cortex, brain stem, and spinal cord. About 10% of all ALS patients are familial cases (FALS), of which 20% have mutations in the Cu, Zn-superoxide dismutase (SOD1) gene. The murine model for FALS, which overexpresses a FALS variant of the SOD1 gene, exhibits progressive limbic paralysis followed by death. Treatment of FALS mice with WHI-P131, a specific inhibitor of Janus kinase 3 (JAK3), increased survival by more than two months, suggesting that specific inhibitors of JAK3 may be useful in the treatment of human ALS. These results uniquely establish JAK3 as a novel molecular target for the treatment of FALS.
Trieu
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Drug Discovery Program, Department of Neurosciences, Hughes Institute, 2665 Long Lake Road, Roseville, Minnesota, 55113, USA.
Liu
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Liu
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XP
Uckun
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FM
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D014644:Genetic Variation; D019833:Genistein / Q000494:pharmacology / Q000627:therapeutic use*; D006579:Heterozygote; D006801:Humans; D053616:Janus Kinase 3; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000235:genetics*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010243:Paralysis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000235:genetics*
D000975:Antioxidants; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011799:Quinazolines; C116180:WHI P131; D019833:Genistein; D013482:Superoxide Dismutase; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3