The treatment of ALS is difficult because of multiple genetic causes and the interplay of genetics and environment as precipitating factors.  However, drugs to counteract the effect of genetic mutations have not yet been found.  The concept of repurposing existing drugs is attractive because much of the Phase I testing in humans has already been done by the manufacturer.  Certain tyrosine kinase inhibitors have been found to have neurotrophic activity.  We tested four drugs for their ability to decrease protein levels of one of the causative genes,Cu, Zn-superoxide dismutase (SOD1). Our rationale was that compounds that reduce expression of the toxic protein would be beneficial to slow onset and/or disease progression.

Test the tyrosine kinase inhibitor, Imatinib mesylate (Gleevec), a drug that is used to treat leukemia and other cancers for its effects on age-of-onset, progression, and end of life  in a mouse model of amyotrophic lateral sclerosis.

 Imatinib mesylate is a tyrosine kinase inhibitor targeting cAbl, PDGFRA, and others.. We tested it and related inhibitors (Dasitinib, Bosutinib, Nilotinib) in a cell-based assay. Only Imatinib decreased levels of soluble G93A-SOD1 with an IC50 of 110 nanomolar.   We then tested Imatinib in a pilot study (12-14 animals per group) in the G93A-SOD1 mouse.  Drug treatment was at a 2.5 mg/kg (IP), daily, beginning at age 60 (~30 days before disease symptoms).

 We found that Imatinib mesylate significantly delayed age-of-onset (p=0.003) and provided improvements in progression (p=0.03) and extending life (p=0.05) of the G93A-SOD1 mouse.