The Uab Research Foundation

Other

Huang-Ge Zhang

John D Mountz

David T Curiel

Tong Zhou

Carl Edwards, Iii

One major problem with adenovirus gene therapy has been the T-cell mediated immune response elicited by inoculation of adenovirus, which leads to rapid clearance of the virus and loss of transgene expression. In the instant invention, the immune response to a virus is prevented by pre-treatment with adenovirus, adenoassociated virus or herpes virus infected antigen-presenting cell (APC) expressing Fas ligand with induced T-cell tolerance. Administration of AdCMVLacZ after tolerance resulted in prolonged expression of LacZ in tolerized animals compared to control treated animals. In control, but not tolerized animals, there was proliferation of CD3 T-cell in the spleen in response to AdCMVLacZ treatment. Tolerance induction is also indicated by decreased production of interferon-&ggr; and IL-2 by peripheral T-cells isolated from treated animals after stimulation with the adenovirus infected APCs. T-cell tolerance is specific for the virus as the T-cell responses to an irrelative virus, mouse cytomegalovirus (MCMV) remained unimpaired. The instant invention utilizes virus specific T-cell tolerance, which is induced by APCs that co-express Fas ligand and virus antigens. The instant invention involves novel vectors and methods to induce tolerance to a viral vector gene therapy and prolong expression of a transgene in a viral host.

Controlling immune response to specific antigens

The present invention provides a method of increasing adenoviral gene expression in a tissue of an animal, comprising the step of administering to said animal a pharmacologically effective dose of tumor necrosis factor binding protein. Also provided is a various method of method of reducing an inflammatory response associated with adenoviral administration in a tissue of an animal, comprising the step of administering to said animal a pharmacologically effective dose of tumor necrosis factor binding protein.

Method for the augmentation of gene expression

The present invention discloses a method of producing large-scale recombinant adeno-associated virus stocks by infection of cells with at least one recombinant adenovirus vector(s). The vector(s) encode a therapeutic gene flanked by the terminal repeat ends of adeno-associated virus and the adeno-associated virus rep and cap genes. Transfection with two recombinant adenovirus vector(s) instead of two plasmids plus adenovirus results in the large scale, high titer production of recombinant adeno-associated virus with little to no contaminating adenovirus present.

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Birmingham, AL, United States of America

Huang-Ge Zhang