by Tom Hoglund
In one of the single most important advances in the history of retinal degeneration research, a group of Foundation Fighting Blindness-supported scientists used gene therapy to restore vision in a canine model of severe childhood blindness, known clinically as Leber congenital amaurosis (LCA). This finding, published in the May issue of Nature Genetics, represents the first time researchers successfully restored vision in a large animal model of retinal degeneration.
Responding to the study findings, Dr. Gerald Chader, Chief Scientific Officer of The Foundation Fighting Blindness, said, “With this study, gene therapy has overcome a major hurdle. Previously, researchers have restored vision in rodents. However, the Food and Drug Administration wants to see evidence that a treatment is safe and effective in a large animal model before granting permission to begin clinical trials in humans. Genetic medicine is now making things we could only once dream of a reality.”
What is LCA?
LCA is the name given to a group of severe, early-onset forms of retinal degeneration. Infants born with LCA have very little if any existing vision and usually develop unusual roving eye movements.
The diagnosis of LCA is confirmed by an electroretinogram (ERG), a medical test that measures the retinaâs response to light. Patients with LCA have almost no detectable ERG readings, indicating near total blindness.
Tragically, only after celebrating the birth of a healthy baby, do parents begin to notice that their child’s eyes move oddly in a roving fashion but do not seem to respond to any visual cues. Once a child is diagnosed with LCA, parents must quickly adapt to an unfamiliar, unexpected and sometimes frightening reality they never anticipated for their child. Baseball bats must be traded for canes; plain white pages punched with Braille replace richly illustrated childrenâs books. In short, LCA literally darkens the dreams and aspirations of both children and parents.
LCA Research Advances
In 1997, Foundation researchers discovered that mutations in the RPE65 gene cause a form of LCA. As its name implies, the RPE65 gene is active in a layer of cells called the retinal pigment epithelium, or RPE for short. RPE cells support the function of photoreceptor cells in the neural retina. In 1998, experiments performed with a rodent model of LCA “developed with funding support from The Foundation”found that the RPE65 gene product supports the phototransduction cycle, the biochemical process that turns light into an electrical signal. Although photoreceptor cells in this form of LCA are thought to be entirely normal, RPE65 mutations in the adjoining RPE cell layer block phototransduction, resulting in blindness. That same year, Foundation supported scientists cloned the canine RPE65 gene and identified the mutation that is responsible for the disease in Briard dogs. This work set the stage for the present breakthrough.
Greater Understanding Leads to Treatment Breakthrough
Applying the knowledge gained from these discoveries, a group of Foundation-supported researchers from Cornell University, University of Pennsylvania and the University of Florida hypothesized that replacing the dysfunctional RPE65 gene with a healthy gene might restore RPE cell function and thereby engage the idle but still healthy photoreceptor cells. Testing this theory, the team treated four Briard dogs, a canine breed that, like humans, is genetically susceptible to this form of LCA.
Twelve weeks after a subretinal injection containing the RPE65 gene and a viral vector to deliver the gene to RPE cells, ERG tests revealed the treated eyes had a remarkable improvement in retinal function. By contrast, untreated eyes had almost no detectable ERG. Behavioral testing revealed that these canines had regained ambulatory vision, seeing well enough to avoid obstacles in their path even under dim lighting conditions.
This study also represents a large collaborative effort with Foundation-supported scientists from different institutions. The team of researchers was led by Drs. Gregory Acland and Gustavo Aguirre from The Foundationâs research center at Cornell University; Drs. Jean Bennett, Albert Maguire, and Samuel Jacobson of the Foundationâs research center at the Scheie Eye Institute, University of Pennsylvania; and Dr. William Hauswirth at the University of Florida. For some candid perspectives by the different researchers on their discovery, please visit The Foundation’s Web site at www.blindness.org.
The Foundation and the vision research community will now concentrate on the steps needed to rapidly advance this gene therapy treatment to human clinical trials. For example, toxicity studies to better gauge the safety of the treatment must be completed. The long-term effectiveness of the treatment must also be evaluated. Patients with RPE65 mutations need to be identified for possible inclusion in a clinical trial. A viral vector suitable for use in humans must be manufactured under rigorous quality control guidelines. A clinical trial protocol must be designed and implemented. A pediatric ophthalmology care facility must be created. While these hurdles present funding challenges, the more formidable science hurdles are now mostly behind us.
Implications For Other Diseases
That researchers can restore vision in the most severe form of retinal degeneration suggests that sight-restoring treatments for other diseases are also possible. As Dr. Jean Bennett, a co-author of the study said, “We have worked hard for many, many years trying to develop a treatment for retinal degeneration, and this is the biggest leap forward yet. These results will expand the possible treatment strategies for a diverse set of retinal degenerative diseases.”
The Foundation is committed to advancing gene therapy and other treatments for all forms of retinal degeneration. This commitment will take an enormous investment on the part of all who support The Foundation in its mission to treat and ultimately cure retinal degenerative diseases. Clearly, we hold the future in our hands.