Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration

James D. Thompson, Douglas J. Kornbrust, Jeffrey W D Foy, Elisabeth C R Solano, David J. Schneider, Elena Feinstein, Bruce Molitoris, Shai Erlich

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)255-264
Number of pages10
JournalNucleic Acid Therapeutics
Volume22
Issue number4
DOIs
StatePublished - Aug 1 2012

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Pharmacokinetics
Intravenous Administration
Toxicology
RNA
Reperfusion Injury
Primates
Rats
Rodentia
Transplantation (surgical)
Delayed Graft Function
Kidney
Apoptosis Regulatory Proteins
Complement Activation
RNA Interference
Acute Kidney Injury
Grafts
Liver
Kidney Transplantation
Surgery
Small Interfering RNA

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Biochemistry
  • Drug Discovery

Cite this

Thompson, J. D., Kornbrust, D. J., Foy, J. W. D., Solano, E. C. R., Schneider, D. J., Feinstein, E., ... Erlich, S. (2012). Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration. Nucleic Acid Therapeutics, 22(4), 255-264. https://doi.org/10.1089/nat.2012.0371

Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration. / Thompson, James D.; Kornbrust, Douglas J.; Foy, Jeffrey W D; Solano, Elisabeth C R; Schneider, David J.; Feinstein, Elena; Molitoris, Bruce; Erlich, Shai.

In: Nucleic Acid Therapeutics, Vol. 22, No. 4, 01.08.2012, p. 255-264.

Research output: Contribution to journalArticle

Thompson, James D. ; Kornbrust, Douglas J. ; Foy, Jeffrey W D ; Solano, Elisabeth C R ; Schneider, David J. ; Feinstein, Elena ; Molitoris, Bruce ; Erlich, Shai. / Toxicological and pharmacokinetic properties of chemically modified siRNAs targeting p53 RNA following intravenous administration. In: Nucleic Acid Therapeutics. 2012 ; Vol. 22, No. 4. pp. 255-264.
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