Toxicological and Pharmacokinetic Properties of Chemically Modified siRNAs Targeting p53 RNA Following Intravenous Administration

• Published in: Nucleic acid therapeutics Vol. 22; no. 4; pp. 255 - 264
• Main Authors: Thompson, James D., Kornbrust, Douglas J., Foy, Jeffrey W-D., Solano, Elisabeth C.R., Schneider, David J., Feinstein, Elena, Molitoris, Bruce A., Erlich, Shai
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 01.08.2012
• Subjects: Administration, Intravenous; Allografts; Animals; Area Under Curve; Blood; Clotting; Complement activation; Data processing; Drug delivery systems; Drug Evaluation, Preclinical; Female; Heart; Heart transplantation; Injuries; Intravenous administration; Ischemia; Kidney; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney transplantation; Kidneys; Liver; Macaca fascicularis; Male; Metabolic Clearance Rate; Molecular biology; Original; Original Articles; p53 protein; Pharmaceutical sciences; Pharmacokinetics; Preservation; Primates; Rats; Rats, Sprague-Dawley; Renal function; Renal Insufficiency - metabolism; Reperfusion; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacokinetics; RNA, Small Interfering - toxicity; RNA-mediated interference; Rodents; Side effects; siRNA; Surgery; Tissue Distribution; Toxicity; Tumor Suppressor Protein p53 - genetics
• DOI: 10.1089/nat.2012.0371
• ISSN: 2159-3337

We report the toxicological and pharmacokinetic properties of the synthetic, small interfering RNA I5NP following intravenous administration in rodents and nonhuman primates. I5NP is designed to act via the RNA interference (RNAi) pathway to temporarily inhibit expression of the pro-apoptotic protein p53 and is being developed to protect cells from acute ischemia/reperfusion injuries such as acute kidney injury that can occur during major cardiac surgery and delayed graft function that can occur following renal transplantation. Following intravenous administration, I5NP was very rapidly cleared from plasma was distributed predominantly to the kidney, with very low levels in liver and other tissues. Doses of 800 mg/kg I5NP in rodents, and 1,000 mg/kg I5NP in nonhuman primates, were required to elicit adverse effects, which in the monkey were isolated to direct effects on the blood that included a sub-clinical activation of complement and slightly increased clotting times. In the rat, no additional adverse effects were observed with a rat analogue of I5NP, indicating that the effects likely represent class effects of synthetic RNA duplexes rather than toxicity related to the intended pharmacologic activity of I5NP. Taken together, these data support clinical testing of intravenous administration of I5NP for the preservation of renal function following acute ischemia/reperfusion injury.