AN ADENOVIRUS VECTOR WITH GENETICALLY-MODIFIED FIBERS DEMONSTRATES EXPANDED TROPISM VIA UTILIZATION OF A COXSACKIEVIRUS AND ADENOVIRUS RECEPTOR-INDEPENDENT CELL ENTRY MECHANISM

Recombinant adenoviruses (Ad) have become the vector system of choice for a variety of gene therapy applications. However, the utility of Ad vectors is limited due to the low efficiency of Ad-mediated gene tran sfer to cells expressing marginal levels of the coxsackievirus and ade novirus receptor (CAR). In order to achieve CAR-independent gene trans fer by Ad vectors in clinically important contexts, we proposed modifi cation of viral tropism via genetic alterations to the viral fiber pro tein. We have shown that incorporation of an Arg-Gly-Asp (RGD)-contain ing peptide in the HI loop of the fiber knob domain results in the abi lity of the virus to utilize an alternative receptor during the cell e ntry process. We have also demonstrated that due to its expanded tissu e tropism, this novel vector is capable of efficient transduction of p rimary tumor cells. An increase in gene transfer to ovarian cancer cel ls of 2 to 3 orders of magnitude was demonstrated by the vector, sugge sting that recombinant Ad containing fibers with an incorporated RGD p eptide may be of great utility for treatment of neoplasms characterize d by deficiency of the primary Ad type 5 receptor.