Effect of dose and plasma concentration on liver uptake and pharmacologic activity of a 2′-methoxyethyl modified chimeric antisense oligonucleotide targeting PTEN

The role of dose and plasma concentration on liver tissue uptake and resulting antisense pharmacology using a chemically modified antisense oligonucleotide (ASO) targeting PTEN was assessed in mice. A single bolus s.c. dose of 60 mg/kg in mice showed a time-dependent reduction in liver PTEN mRNA that was maximal at 48–72 h and returned to near control levels by 20 days after administration. These pharmacodynamics are in good agreement with liver concentrations of ASO and are consistent with slow elimination (t1/2 = 8 days) of the PTEN ASO from Balb/C mouse liver. As expected, highest ASO concentrations in liver resulted from the s.c. slow infusion at all doses tested. Unexpectedly, the liver EC50 for the 24-h s.c. slow infusion was approximately twofold higher than the two bolus routes of administration. Based on plasma concentration analysis it appears that 1–2 μg/mL ASO plasma concentration is a threshold that, if exceeded, results in robust antisense effects and below which there is reduced or complete loss of antisense pharmacology in liver even though bulk uptake in the organ is improved. Co-administration of a nonsense ASO competed for liver uptake, but unexpectedly increased pharmacodynamic response for the active oligonucleotide (ISIS 116847) supporting inhibition of a nonproductive bulk uptake pathway while simultaneously improving productive uptake (pharmacodynamics). This competition effect was similar whether the nonsense oligonucleotide was co-administered with ASO or administered up to 24 h prior to active ASO injection.

Graphical abstractRate and route of administration, and ultimate plasma concentration, alter the effective uptake of antisense oligonucleotide in mouse liver.Figure optionsDownload full-size imageDownload as PowerPoint slide