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 neurodegenerati ve disorder involving the motor neurons of cortex, brain stem, and spinal c ord. 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 mo del for FALS, which overexpresses a FALS variant of the SOD1 gene, exhibits progressive limbic paralysis followed by death. Treatment of FALS mice wit h WHI-P131, a specific inhibitor of Janus kinase 3 (JAK3), increased surviv al 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. (C) 2000 Academ ic Press.