Two groups of investigators have reported independently on their initial observations from Phase I clinical trials of gene transfer for Leber congenital amaurosis (LCA) caused by mutations in the RPE65 gene. The two papers appear in the April 27, 2008, online version of the New England Journal of Medicine. A third Phase I clinical trial, one supported directly by the National Eye Institute (NEI) of the National Institutes of Health (NIH), is ongoing, but initial observations have yet to be published. These Phase I clinical trials are designed as a preliminary assessment of the safety of gene transfer techniques in treating people with LCA.

People with LCA are born with severe visual impairment or develop vision loss early in childhood. "Proof-of-concept" studies in animal models of LCA demonstrated gene transfer techniques to be safe, effective, and long-lasting in restoring visual function. NEI has supported much of the basic, translational, and pre-clinical research leading up to these Phase I trials. For extensive background information on gene transfer and LCA, go to: http://www.nei.nih.gov/lca/.

The initial observations indicate that within a short follow-up period, five months to one year, gene transfer for LCA appears to be well-tolerated and safe. Phase I clinical trials are specifically designed to evaluate safety; they do not feature the standard statistical and methodological safeguards required to properly evaluate treatment effectiveness. Nonetheless, several of the reported observations suggest that gene transfer may be exerting modest effects in some of the treated individuals. Additional follow-up testing of the treated individuals should determine whether these effects are sustained. Durability of effects is crucial given the history of human gene therapy trials which have demonstrated that early gene expression can be thwarted by immunologic or other responses.

No conclusions can be made at present as to whether gene transfer will restore visual function in people with LCA or impede further progression of the disease. Additional important insights will be gained when investigators have the opportunity to examine the totality of the published data, including observations from the third Phase I clinical trial. These insights will enable investigators to refine the gene transfer techniques and will provide the preliminary information needed to design the Phase II and Phase III clinical trials that are necessary to determine both safety and effectiveness in a rigorous way.