A study of the purine derivative AIT-082 in G93A SOD1 transgenic mice.
AIT-082 is a purine derivative with neuroprotective and neurotrophic activity that is desirable in a candidate therapy for Amyotrophic Lateral Sclerosis. Consequently, we investigated the effect of AIT-082 in a transgenic mouse model of ALS. AIT-082 (0, 1, 3, 10, 30, 60, 100 mg/kg) was given to TgN(SOD1-G93A)1Gur transgenic mice from age 30 days until death. The age at onset of clinical signs of disease and the age at death were recorded for each animal. Disease progression was measured by the weekly average distance run in a running wheel. Analysis was made by the Kaplan Meier method with log rank statistics, log rank for trend and Cox regression. Neuropathological study of the brain, spinal cord, muscles and other organs was undertaken at death. In a second experiment we studied the effect of AIT-082 (30 mg/kg) at the onset of disease and during survival of transgenic G93A SOD1 mice, beginning dosing at different ages (20, 30, 40, 60, 80 days). Disease onset was mildly earlier (i.e. worse) at 1 and 10 mg/kg AIT-082 and mildly delayed at 30 mg/kg. This improvement did not reach the usual statistical significance. There was no difference in the age at death for any treatment dose. There was no difference in the neuropathology of treated and untreated G93A mice. However, there was an early improvement in the running wheel function at all tested doses. Using Cox regression, after adjustment for sex, the mice in the running wheels had slightly delayed onset of disease without change in survival and, after adjustment for exercise, the female mice had slightly improved survival. Consequently, AIT-082 would not be an attractive candidate for ALS clinical trials as monotherapy and justification for its use in combination therapy would require additional laboratory support. There was dissociation between the endpoints of disease progression (as judged by running wheel performance) and disease onset and survival. AIT-082 improved early running wheel performance yet led to accelerated late decline and had no impact on survival. It is possible that the drug facilitates early sprouting that leads to accelerated late decline.
Jiang
F
F
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Li
W P
WP
Kwiecien
J
J
Turnbull
J
J
D062365:Aminobenzoates / Q000627:therapeutic use*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007042:Hypoxanthines / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
D062365:Aminobenzoates; D007042:Hypoxanthines; D018696:Neuroprotective Agents; C086241:4-((3-(1,6-dihyro-6-oxo-9H-purin-9-yl)-1-oxopropyl)amino)benzoic acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1