Gene Therapy in Corneal Transplantation

George A. J. T., Larkin D. F. P.,
Department of Immunology, Imperial College of Science, Technology and Medicine, Hammersmith Hospital (London)

Corneal transplantation affords a good model for the development of gene therapy approaches to prevent or treat inflammation. The cornea has a relative simple anatomy, allowing easy access of vectors to the endothelium. In addition the organ can be cultured ex vivo for prolonged periods, allowing for manipulation prior to transplantation. We have used a number of viral vectors to transduce the cornea with both marker genes and therapeutic genes. Thus, for example, we have used adenoviral vectors to deliver soluble version of CTLA4 and the TNF receptor to block the inflammatory response. However, these have the disadvantage of being inflammatory in nature, and we have shown reduced graft survival following treatment with control adenovirus. We have therefore concentrated on using non-viral vectors, in particular lipsomes and dendrimers. We have used a variety of methods to improve the ability of these vectors to deliver DNA to the endothelium, most notably antibodies to target the vectors to particular antigens on the cell surface. We have also developed novel therapeutic genes, for example using intracellular antibodies to abolish expression of adhesion molecules on the surface of cells or using surface tethered antibodies against CTLA4 to inhibit T cell responses. This highlights the importance of the cornea not only as a therapeutic target in its own right, but alsoas a model for the treatment of other inflammatory diseases.

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