Recovery of sight realized after gene-based treatment in most severe form of retinal degeneration

(Philadelphia, PA) -- Researchers from Scheie Eye Institute at the University of Pennsylvania Medical Center have developed a gene therapy protocol that successfully restored sight in dogs afflicted with a variation of Leber congenital amaurosis (LCA) -- a severe form of retinal degeneration that, in humans, renders infants permanently blind. The work was done in collaboration with researchers from Cornell University (who discovered the mutated gene in dogs) and the University of Florida (who helped establish the adeno-associated vector delivery vehicle). The study will appear in the May issue of Nature Genetics.

Much progress has been made in identifying the genetic basis of retinal degeneration, making it possible to test new treatments that target the fundamental defects that cause such conditions. This testing is aided by the identification of strains of animals -- including mice and dogs -- which have blindness caused by the identical genetic defects that occur in humans with similar symptoms.

Under optimum conditions, normal protein transports a Vitamin A-like compound to the retina, which is necessary for sight. In some cases of animal and human LCA, wild-type RPE65 -- the protein that transports the necessary Vitamin A- like compound is missing from the gene, which results in blindness.

According to Jean Bennett, MD, PhD, researcher at the F.M. Kirby Center for Molecular Ophthalmology at Penn's Scheie Eye Institute and a senior co-author of the study, previous studies to reverse blindness in rodents have been successful, but this is the first successful outcome using larger animals. "The results are spectacular -- in fact, they are the sort of findings that a scientist usually only hopes to, but rarely does, see, in the course of a career," she explains. "This study takes a great stride forward in demonstrating that gene therapy does not just slow down a retinal degenerative disease, but can actually provide recovery of vision to an animal that was previously blind."

In the Penn study, researchers injected a recombinant adeno-associated virus (AAV) carrying wild-type RPE65 intra-occularly into the area between the photoreceptors and the retinal pigment epithelium of three dogs. The consequences of this injection were assessed through an electroretinogram, which showed, 90 days after injection, the waveforms of the treated eye to be similar in scope to that of a sighted dog's eyes. The assessment presently continues at regular intervals.

Qualitative visual assessment of the three treated dogs took place four months after the injection occurred. Results of behavioral testing were consistent with the electrophysiological results. The treated dogs all avoided collision with objects in front and to the right (the side injected); yet consistently collided with objects to the left. In contrast, the untreated dog did not display avoidance behavior in any direction.

The diagnosis of this devastating disease usually begins with the patient's parents, who notice soon after birth that their child has roving eye movements and apparently doesn't see. Confirmation of the disease by an ophthalmologist or retina specialist via an electroretinogram (ERG) studies the electrical activity of the retina in response to light. These studies reveal grossly abnormal or absent responses where, normally, there is a waveform similar to an EKG tracing. With the patient resigned to a life of special schooling, canes, guide dogs, and Braille, the disease results in significant hardship and morbidity for the child, the family and for society.

"We have worked hard for many, many years to develop a treatment for retinal degeneration, and this is the biggest leap forward yet," states Bennett. "However, we are nowhere near the introduction of the missing protein in humans to restore sight,"

"While this may prove to be the treatment method used for other forms of retinal disease, such as macular degeneration, this particular therapy is useful only for LCA," adds co-author, Albert Maguire, MD.

Researchers who collaborated with Bennett and Maguire include Penn researcher Samuel Jacobson, MD, PhD; Cornell University researchers Gregory Acland, VMD, and Gustavo Aguirre, VMD, PhD; and University of Florida researcher William Hauswirth, PhD.


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Editor's note: Dr. Bennett will be out of town until Wednesday, May 2, 2001; however, you can reach her by calling the Department of Public Affairs, at 215-662-2560.

To determine if this discovery is of relevance to you or your family, please contact:
The Center for Hereditary Retinal Degenerations Director, Samuel G. Jacobson, MD, PhD
Scheie Eye Institute 215-662-9981



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