SAFETY AND SHORT-TERM TOXICITY OF A NOVEL CATIONIC LIPID FORMULATION FOR HUMAN GENE-THERAPY

Among the potential nonviral vectors for human gene therapy are DNA-li posome complexes. In a recent clinical study, this delivery system has been utilized. In this report, a novel cationic lipid, dimyristyloxyp ropyl-3-dimethyl-hydroxyethyl ammonium (DMRIE), has been substituted i nto the DNA-liposome complex with dioleoyl phosphatidylethanolamine (D OPE), which both improves transfection efficiencies and allows increas ed doses of DNA to be delivered in vivo. The safety and toxicity of th is DNA-liposome complex has been evaluated in two species, mice and pi gs. The efficacy of DMRIE/DOPE in inducing an antitumor response in mi ce after transfer of a foreign MHC has been confirmed. No abnormalitie s were detected after administration of up to 1,000-fold higher concen trations of DNA and lipid than could be tolerated in vivo previously. Examination of serum biochemical enzymes, pathologic examination of ti ssue, and analysis of cardiac function in mice and pigs revealed no to xicities related to this treatment. This improved cationic lipid formu lation is well-tolerated in vivo and could therefore allow higher dose administration and potentially greater efficiency of gene transfer fo r gene therapy.