CANCER GENE-THERAPY USING PLASMID DNA - SAFETY EVALUATION IN RODENTS AND NONHUMAN-PRIMATES

To evaluate the safety of a plasmid DNA-lipid complex, a series of good laboratory practice (GLP) safety studies were conducted with VCL-1005, a plasmid DNA expression vector containing both the human class I MHC HLA-B7 heavy-chain and the beta(2)-microglobulin (beta(2)m) light-chain genes formulated with the cationic lipid, DMRIE/DOPE, In mice, the repeated intravenous injection of VCL-1005 at plasmid DNA doses of 0.1, 1.0, or 10 mu g for 14 days had only incidental effects on clinical chemistry and hematology, and did not result in any organ pathology, Repeated intrahepatic injections of VCL-1005 in mice did not result in significant liver histopathology or significant alterations in liver enzymes, In cynomolgus monkeys, the repeated intravenous administration of VCL-1005 at a cumulative dose of 720 mu g of DNA had no effects on clinical chemistry, hematology, or organ pathology, Thus, systemic administration of a plasmid DNA expression vector containing the coding sequence for a foreign MHC class I molecule did not result in significant toxicity or a pathological immune response in animals, These results suggest that the direct transfer of VCL-1005, a plasmid DNA-lipid complex, could be used for the safe in vivo delivery of recombinant DNA for a cancer gene therapy trial.