Abstract 715: Vivo-Morpholino antisense oligomers decrease tumor growth in mice by altering mVEGF mRNA splicing to knock down mVEGF expression

Abstract

Abstract Vivo-Morpholino antisense oligomers can knock down gene expression by altering splicing of the pre-mRNA and generating a translational frameshift. VEGF overexpression is crucial for tumor growth and anti-VEGF therapies are promising in the treatment of certain cancers. Decreasing VEGF gene expression by exon deletion using Vivo-Morpholinos could suppress tumor growth. We examine the efficiency of mVEGF exon 2 deletion and tumor growth inhibition in mice injected with a Vivo-Morpholino oligomer (VMO-e2i2), which is designed to specifically delete the mVEGF exon 2 and cause downstream frameshifting in mVEGF protein. Mice bearing s.c. Lewis lung carcinoma tumors are I.V. injected with the VMO-e2i2 oligomers at 15mg/kg twice weekly for 2 weeks. VEGF exon 2 deletions are detected by RT-PCR in various tissues tested: approximately 100% exon 2 deletion in kidney, 80% in liver, 70% in skeletal muscles and 40% in s.c. tumors. The tumor volumes decrease by 6 fold over 16 days in mice injected with the VMO-e2i2 oligomers. Exon deletions are detected in various tissues including liver, small intestine, colon, skeletal and cardiac muscles, lung, stomach and kidney. The exon deletion mediated by Vivo-Morpholinos is target specific, dose-dependent and is detectable for more than 15 weeks after a single IV injection in mice. No significant toxicity is observed in mice injected with the effective dosage. Vivo-Morpholinos therefore represent a useful tool for cancer target identification and validation in rodent models and a possible therapeutic treatment. Citation Format: Shan Jiang. Vivo-Morpholino antisense oligomers decrease tumor growth in mice by altering mVEGF mRNA splicing to knock down mVEGF expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 715. doi:10.1158/1538-7445.AM2014-715