Dose-Finding Study and Pharmacokinetics Profile of the Novel 13-Mer Antisense miR-221 Inhibitor in Sprague-Dawley Rats

Molecular Therapy. Nucleic Acids
Maria Teresa Di MartinoPierfrancesco Tassone

Abstract

miR-221 is overexpressed in several malignancies where it promotes tumor growth and survival by interfering with gene transcripts, including p27Kip1, PUMA, PTEN, and p57Kip2. We previously demonstrated that a novel 13-mer miR-221 inhibitor (locked nucleic acid [LNA]-i-miR-221) exerts antitumor activity against human cancer with a pilot-favorable pharmacokinetics and safety profile in mice and non-naive monkeys. In this study, we report a non-good laboratory practice (GLP)/GLP dose-finding investigation of LNA-i-miR-221 in Sprague-Dawley rats. The safety of the intravenous dose (125 mg/kg/day) for 4 consecutive days, two treatment cycles, was investigated by a first non-GLP study. The toxicokinetics profile of LNA-i-miR-221 was next explored in a GLP study at three different doses (5, 12.5, and 125 mg/kg/day). Slight changes in blood parameters and histological findings in kidney were observed at the highest dose. These effects were reversible and consistent with an in vivo antisense oligonucleotide (ASO) class effect. The no-observed-adverse-effect level (NOAEL) was established at 5 mg/kg/day. The plasma exposure of LNA-i-miR-221, based on C0 (estimated concentration at time 0 after bolus intravenous administration) and area un...Continue Reading

Associated Clinical Trials

Citations

Jan 7, 2021·Cancer Gene Therapy·Dan ChenEnhong Xing
Apr 4, 2021·Cancers·Maria Teresa Di MartinoPierfrancesco Tassone

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Methods Mentioned

BETA
antisense oligonucleotide
dissection
xenograft
antisense oligonucleotides

Software Mentioned

Aptuit
CiToxLAB
Phoenix WinNonlin
PathData

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