Specific organ gene transfer in vivo by regional organ perfusion with herpes viral amplicon vectors: Implications for local gene therapy

Background. Many gene therapy strategies would benefit from efficient, regi onal organ delivery of therapeutic genes. Methods. Regional perfusions of lung, liver or bladder were performed to de termine if rapid and efficient gene transfer can be accomplished in vivo, a nd to deter mine if in vivo gene transfer can be limited to the organ of in terest. In addition, herpes simplex virus' tumor necrosis factor (HSVtnf), carrying the human tumor necrosis factor alpha gene was used as a treatment for methylcholanthrene sarcoma in a syngeneic lung metastases model in Fis her rats. Results. A 20-minute perfusion using HSV carrying beta -galactosidase (HSVl ac) produced significant expression of this marker gene isolated to the tar get organs, without organ-specific tissue injury or inflammation. Regional perfusion of organs with HSV carrying the cytokine gene tumor necrosis fact or a also resulted in high-level local organ production of this cytokine (2 851 +/- 53 pg/g tissue in perfused lung versus 0 for the contralateral lung ). For the current vector construct, expression of the gene of interest pea ked between 2 and 4 days and was undetectable by 2 weeks after perfusion. I n animals undergoing perfusion as treatment for pulmonary sarcoma, there wa s no difference between tumor counts in lungs perfused with HSVlac (17 +/- 6) or HSVtnf (22 +/- 8), but either treatment resulted in lower tumor count s than controls (111 +/- 24 nodules per lung, P <. 02). Conclusions. Regional organ perfusion using herpes viral vectors is an effe ctive and well-tolerated in vivo method of transiently, delivering potentia lly toxic gene products to target organs in directing gene therapy. Regiona l lung perfusion with HSV amplicons reduces tumor burden in a mt model of p ulmonary metastases, though HSVtnf cannot be demonstrated to augment the cy topathic effect of the HSV amplicon alone in the current model.