title: 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.
authors: 1 Quark Pharmaceuticals, Inc. , Boulder, Colorado.
authors: Elisabeth C R
authors: EC
authors: Solano
authors: Douglas J
authors: DJ
authors: Kornbrust
authors: Amber
authors: A
authors: Beaudry
authors: Jeffrey W-D
authors: JW
authors: Foy
authors: David J
authors: DJ
authors: Schneider
authors: James D
authors: JD
authors: Thompson
mesh_terms: D000818:Animals; D058256:Brain Waves / Q000502:physiology; D053143:Caspase 2 / Q000235:genetics* / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D007275:Injections, Intravenous; D058449:Intravitreal Injections; D007928:Lethal Dose 50; D008297:Male; D058990:Molecular Targeted Therapy; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053143:Caspase 2