Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four-week study in cynomolgus monkeys

Synthetic Oligonucleotides: The Development of Antisense Therapeutics

“…However, these same cells reponded to a primate-specific oligonucleotide by specific reduction in target mRNA and protein levels. In a 4-wk toxicology study with cynomolgus monkeys, the human c-raf antisense oligonucleotide did not demonstrate reduction in levels of target mRNA (31 (16,19,31 ). Therefore, there were no effects evident that might be solely attributed to a reduction of a specific mRNA.…”

“…Therefore, there were no effects evident that might be solely attributed to a reduction of a specific mRNA. The acute effects involving inhibition of coagulation and activation of complement have been well characterized (12,17,20 (16,23,29). The renal effects occur at doses well in excess of those used in clinical trials, and little if any alteration in renal function is evident (23,29 …”

Molecular strategy using cis-element ‘decoy’ of E2F binding site inhibits neointimal formation in porcine balloon-injured coronary artery model

“…22 Liver enzymes may also be increased in animals treated with moderate to high doses. Several phosphorothioate ODN have been shown to cause acute hypotensive events in monkeys, 23,24 probably due to complement activation. 25 This toxicity can be avoided by giving intravenous infusions rather than bolus injections.…”

Reduction of liver tumor necrosis factor‐α expression by targeting delivery of antisense oligonucleotides into Kupffer cells protects rats from fulminant hepatitis

“…Parenchymal cells are not a unique cell in the animal liver and Kupffer cells comprise another type of cell that express ASGPr [40]. From the anatomical structure of the liver, we can see that Kupffer cells are localized in the sinusoids, whereas parenchymal cells are situated behind a fenestrated endothelium [13].…”