Leber’s congenital amaurosis (LCA) is a form of blindness that affects about 1 in 80,000 people. This inherited disease, in which the retina progressively degenerates, results in severe loss of vision, and frequently patients can only see well enough to count fingers or see bright lights. Unfortunately, many of these patients also experience eye pain from bright lights. LCA is caused by mutations in a number of genes, including the RPE65 gene. Currently, there is no treatment for this disease but clinical trials using gene therapy have recently shown some promise.
The ability to deliver a gene using viral gene therapy was successfully demonstrated in rats and mice in the 1990’s. Given these technical capabilities, it seemed that LCA might be a good target for gene therapy – delivery of the vector to the small space below the retina could deliver a normal copy of the gene exactly where it is needed. The next question was, could vision loss be prevented in animal models of LCA? Briards, a type of sheepdog, are predisposed to blindness, and genetic testing showed they often have mutations in RPE65, just like LCA patients. Delivery of RPE65 using viral gene therapy to these afflicted dogs gave encouraging results: the dogs had improved vision as shown by their electroretinograms and their ability to navigate obstacle courses in dim light (Acland et al., 2001).
Now, a report in the Human Gene Therapy and a commentary appearing in both the New England Journal of Medicine and Scientific American highlight a Phase 1 clinical trial to treat LCA using viral delivery of a normal copy of RPE65(Cideciyan et al., 2009). Within weeks of receiving the vector, all three patients could detect dim light, a task they could not previously do. Importantly, these visual improvements were still apparent 1 year after treatment. Phase 1 clinical trials are specifically designed to test safety of a treatment and to date, viral gene delivery of RPE65 has passed this test. These three patients have not developed an immune response to the viral delivery system, a critical aspect for efficacy and safety of the treatment.
Studies in animals are also helping to clarify how and when the treatment will be effective. An important consideration is that people or animals need to have a good number of retinal cells left if the gene therapy is to be effective: this treatment only works before retinal degeneration has progressed too far. The patients in the clinical trials were adults with some intact photoreceptors, however most LCA patients lose photoreceptors in early childhood. Studies using mice or dogs of various ages have shown promising results indicating that the younger the animal is treated, they more effective treatment is (Dejneka et al., 2004) . Consequently, early intervention, before extensive degeneration has occurred, will likely be critical to preventing the severe loss of vision that characterizes this disease. Additional Phase 1 clinical trials are ongoing and include children with LCA.
Can thes patients that have received RPE65 through gene therapy expect the same prognosis as their canine counterparts? Only time will tell, but they should be optimistic about their long-term outcomes. The LCA briard dogs, including Lancelot who was one of the first dogs treated, have shown functional recovery that lasting for more than 7 years.
Acland, G.M., Aguirre, G.D., Ray, J., Zhang, Q., Aleman, T.S., Cideciyan, A.V., Pearce-Kelling, S.E., Anand, V., Zeng, Y., Maguire, A.M., et al. (2001). Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28, 92-95.
Cideciyan, A.V., Hauswirth, W.W., Aleman, T.S., Kaushal, S., Schwartz, S.B., Boye, S.L., Windsor, E.A., Conlon, T.J., Sumaroka, A., Pang, J.J., et al. (2009). Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year. Hum Gene Ther.
Dejneka, N.S., Surace, E.M., Aleman, T.S., Cideciyan, A.V., Lyubarsky, A., Savchenko, A., Redmond, T.M., Tang, W., Wei, Z., Rex, T.S., et al. (2004). In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther 9, 182-188.