Antisense gene therapy of brain cancer with an artificial virus gene delivery system

Abstract

Therapeutic genes are delivered to the nuclear compartment of cancer cells following intravenous administration with a non-immunogenic "artificial virus" gene delivery system that uses receptor-specific monoclonal antibodies (MAb) to navigate the biological barriers between the blood and the nucleus of the cancer cell. Mice implanted with intracranial U87 human glial brain tumors are treated with a nonviral expression plasmid encoding antisense mRNA against the human epidermal growth factor receptor gene (EGFR). The plasmid DNA is packaged within the interior of polyethylene glycol-modified (PEGylated) immunoliposomes, and delivered to the brain tumor with MAbs that target the mouse transferrin receptor (TRFR) and the human insulin receptor (INSR). The mouse TRFR MAb enables transport across the tumor vasculature, which is of mouse brain origin, and the INSR MAb causes transport across the plasma membrane and the nuclear membrane of the human brain cancer cell. The lifespan of the mice treated weekly with an intravenous administration of the EGFR antisense gene therapy packaged within the artificial virus is increased 100% relative to mice treated either with a luciferase gene or with saline.