Toxicological and pharmacokinetic properties of QPI-1007, a chemically modified synthetic siRNA targeting caspase 2 mRNA, following intravitreal injection

Nucleic Acid Ther. 2014 Aug;24(4):258-66. doi: 10.1089/nat.2014.0489.


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.

MeSH terms

  • Animals
  • Brain Waves / physiology
  • Caspase 2 / genetics*
  • Caspase 2 / metabolism
  • Drug Administration Schedule
  • Female
  • Injections, Intravenous
  • Intravitreal Injections
  • Lethal Dose 50
  • Male
  • Molecular Targeted Therapy
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / chemical synthesis
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacokinetics*
  • Rabbits
  • Rats
  • Rats, Sprague-Dawley
  • Retina / metabolism


  • RNA, Messenger
  • RNA, Small Interfering
  • Caspase 2