PHILADELPHIA -- Researchers at the University of Pennsylvania have demonstrated that gene therapy used to restore retinal activity to the blind also restores function to the brain's visual center, a critical  component of seeing.  

The multi-institutional study led by Geoffrey K. Aguirre, assistant professor of neurology in Penn's School of Medicine,  shows that gene therapy can improve retinal, visual-pathway and visual-cortex responses in animals born blind and has the potential to do the same in humans.

"The retina of the eye captures light, but the brain is where vision is experienced," Aguirre said.  "The traditional view is that blindness in infancy permanently alters the structure and function of the brain, leaving it unable to process visual information if sight is restored.  We've now challenged that view."

The results support the potential for human benefit from retinal therapies aimed at restoring vision to those with genetic retinal disease.

Researchers used functional MRI to measure brain activity in blind dogs born with a mutation in gene RPE65, an essential molecule in the retinoid-visual cycle.  The same mutation causes a blindness in humans called Leber congenital amaurosis, or LCA.  It is the first human eye-retinal disorder slated for gene therapy.

Gene therapy, performed by introducing a working copy of RPE65 into the retina, restored eye function in canines.  Yet, it was previously unclear if the brain could "receive" the restored sight.

The team found that gene therapy to the eye dramatically increased responses to light within the visual cortex of the canine brain.  The recovery of visual brain function occurred in a canine that had been blind for the first four years of its life, and recovery was found to persist in another dog for at least two-and-a-half years after therapy, suggesting a level of permanence to the treatment.

Penn scientists then studied the structure and function of the visual brain of human patients with the same form of blindness.  Young adults with blindness from RPE65 mutation had intact visual brain pathways with nearly normal structure.  The Penn team also found that, while the visual cortex of these patients with LCA did not respond to dim lights, the brain's reaction to brighter lights was comparable to that of individuals with normal sight.

"It seems these patients have the necessary brain pathways ready to go if their eyes start working again," Aguirre said.

The results of the current study are critical to these human clinical trials, led at Penn's Scheie Eye Institute by Samuel G. Jacobson, professor of ophthalmology, and Artur V. Cideciyan, research associate professor of ophthalmology.

"Existence of functional potential both in the eye and brain are prerequisites for successful gene therapy in all forms of LCA," Cideciyan said.  "In the RPE65 form of the disease, we now have evidence for both, and treatment at the retinal level has the hope of recovery of useful vision in patients."

Findings of the study were reported in the journal PLoS Medicine.

The study was conducted by Aguirre and Marc Korczykowski of the Department of Neurology in Penn's School of Medicine; Cideciyan, Tomas S. Alemn, Alejandro J. Roman and Samuel G. Jacobson of the Department of Ophthamology; Brian B. Avants and James C. Gee of the Department of Radiology; David H. Brainard of the Department of Psychology in Penn's School of Arts and Sciences; Andrs M. Komromy and Gustavo D. Aguirre of Penn's School of Veterinary Medicine; Gregory M. Acland of the Baker Institute of the College of Veterinary Medicine at Cornell University; and William W. Hauswirth of the University of Florida's Department of Ophthalmology, who created the vector used for the gene therapy.

The research was supported by the National Institutes of Health, the Foundation Fighting Blindness, the Macula Vision Research Foundation, The Chatlos Foundation, the Alcon Research Institute, the Ruth and Milton Steinbach Fund, the The ONCE International Prize for Research and Development in Biomedicine and New Technologies for the Blind, the Macular Disease Foundation and the Burroughs-Wellcome Fund.