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

Abstract

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 2 protein and is being developed as a neuroprotectant for the treatment of nonarteritic anterior ischemic optic neuropathy and other optic neuropathies such 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 administrations of up to 11 doses over 9 months. Test-article-related effects were limited to the eyes, with minimal to mild vitreal cellular infiltration being the major finding, which was reversible. In repeated-dose studies, a modest reduction in B-wave amplitude obtained by electroretinography was observed in animals treated with the highest dose level tested (3 mg, which is equivalent to a 12 mg/eye human dose) that was not considered to be clinically meaningful. Administration in the rat of either a single bolus intravenous (i.v.) injection of 100 mg/kg or daily bolus i.v. injections of 75 mg/kg/day for 28 days failed to elicit any macroscopic or microscopic changes, suggesting a low risk for systemic toxicity. QPI-1007 was negative in three genetic toxicity studies. Overall, the nonclinical studies support the further development of QPI-1007.

Chemical modifications of nucleic acid drugs and their delivery systems for gene‐based therapy

“…QPI‐1007 is a chemically modified synthetic siRNA drug that is designed to target Caspase‐2 mRNA . The antisense ribonucleotide strand of QPI‐1007 is partially substituted with 2′‐ O ‐methyl nucleotides to prevent nuclease degradation and decrease seed region mediated off‐target activity.…”

Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

“…Although there have been no reports to date that Keap1 siRNA is effective in in vivo retinal disease models, other siRNA-based drugs are being tested in clinical ophthalmological trials. QPI-1007 is new synthetic siRNA designed to inhibit caspase 2 expression and has been tested in patients with nonarteritic anterior ischemic optic neuropathy and other optic neuropathies [66]. PF-655 (REDD14NP/RTP801i) is an siRNA that targets the RTP801 (DDIT4/Redd1) gene, which is induced under hypoxia and cellular stress and inhibits the mTOR pathway.…”

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

“…J. Transplant., abstract; V. Peddi et al., 2014, Transplantation, abstract), non-arteritic anterior ischemic optic neuropathy (NAION), 5 diabetic macular edema (DME), 6 hypercholesterolemia, 7 cancer,8, 9 Ebola, 10 and hepatitis B 11 …”