Ocular gene therapy: experimental studies and clinical possibilities.

The Human Genome Project will identify, map and sequence all 50,000-100,000 human genes and will provide the tools to determine the genetic basis of both common and rare diseases. Understanding the genetic basis of human disease will allow for the development of highly specific drugs and for replacement of the altered gene through gene therapy. Gene therapy may also be used to introduce a new function into cells with resulting therapeutic benefit. Genes may be delivered into cells in vitro or in vivo utilizing viral or nonviral vectors. Viral vectors which have been used include retroviruses, adenoviruses, adeno-associated viruses and herpes viruses. Ocular disorders with the greatest potential for benefit of gene therapy at the current time include hereditary ocular diseases, including retinitis pigmentosa, tumors such as retinoblastoma or melanoma, and acquired proliferative and neovascular retinal disorders. We have demonstrated the feasibility of ocular gene therapy in a rabbit model of proliferative vitreoretinopathy, using retroviral vectors containing the herpes simplex virus thymidine kinase 'suicide' gene. Although in vivo transduction efficiency is low, the strong bystander effect results in prominent killing of proliferating cells in this model leading to inhibition of disease. In the future, gene therapy has the potential for the replacement of defective gene products or introduction of new gene products into ocular cells. The selection of appropriate target genes and cells will be critical, as will the development of a methodology for safe, targeted gene transfer.