Toxicological and Pharmacokinetic Properties of QPI-1007, a Chemically Modified Synthetic siRNA Targeting Caspase 2 mRNA, Following Intravitreal Injection

We report the toxicological and pharmacokinetic properties of the synthetic, small interfering RNA(siRNA), QPI-1007, following intravitreal administration. QPI-1007 is a chemically modified siRNA designed to act via the RNA interference(RNAi) pathway to temporarily inhibit expression of the caspase 2protein and is being developed as a neuroprotectant for the treatment of nonarteritic anterior ischemic optic neuropathyand other optic neuropathiessuch as glaucoma that result in the death of retinal ganglion cells. The half-life of QPI-1007 in the vitreous and retina/choroid in the Dutch Belted rabbit was about 2 days, and there was no sign of accumulation after repeated administrations at either 2- or 4-week dosing intervals in the rabbit. QPI-1007 was well tolerated in Dutch Belted rabbits following single or repeated intravitreal administrationsof up to 11 doses over 9 months. Test-article–related effects were limited to the eyes, with minimal to mild vitreal cellular infiltrationbeing the major fi...