Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration.
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.
Quark Pharmaceuticals, Inc., Boulder, Colorado 80301, USA. jthompson@quarkpharma.com
James D
JD
Thompson
Douglas J
DJ
Kornbrust
Jeffrey W-D
JW
Foy
Elisabeth C R
EC
Solano
David J
DJ
Schneider
Elena
E
Feinstein
Bruce A
BA
Molitoris
Shai
S
Erlich
D061605:Administration, Intravenous; D000818:Animals; D019540:Area Under Curve; D004353:Drug Evaluation, Preclinical; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000378:metabolism; D014018:Tissue Distribution; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53