August 4, 2015
NEI
Images of the brain generated by diffusion tensor imaging, a type of MRI. The red highlights show visual pathways in the brain that deteriorate in patients with LCA, but appear to improve with gene therapy to the retina. Credit: Dr. Manzar Ashtari, University of Pennsylvania.

Images of the brain generated by diffusion tensor imaging, a type of MRI. The red highlights show visual pathways in the brain that deteriorate in patients with LCA, but appear to improve with gene therapy to the retina. Credit: Dr. Manzar Ashtari, University of Pennsylvania.

When people lose the ability to see, how do the visual parts of the brain change in response? And if they regain their sight, are the changes reversed? Researchers at the University of Pennsylvania took a rare opportunity to address these questions by looking at how the brains of people with a genetic, blinding eye disease—Leber’s congenital amaurosis (LCA)—responded to an experimental gene therapy.

The group was led by Manzar Ashtari, Ph.D., and Jean Bennett, M.D., Ph.D., who are both researchers at the Center for Advanced Retinal and Ophthalmic Therapeutics (CAROT) in the Department of Ophthalmology at the University of Pennsylvania. Dr. Bennett is a professor of ophthalmology and cell biology at U Penn’s Perelman School of Medicine and the director of CAROT.

The researchers used a type of magnetic resonance imaging (MRI) to uncover deep brain pathways in LCA patients who had received gene therapy to one eye 1-3 years earlier. Their findings suggest that restoring cells and their functions in the eye can also restore brain pathways involved in vision. The findings were published in the journal Science Translational Medicine on July 15.

“This work involved sophisticated brain imaging,” said Cheri Wiggs, Ph.D., who directs programs in psychophysics and low vision at the National Eye Institute, which helped fund the study. “The findings are particularly exciting because they reveal structural & functional changes in the adult brain based on visual experience.” The oldest patient in the study was 45.

Dr. Bennett began a trial of gene therapy for LCA in 2007 with collaborator Albert Maguire, M.D., also a professor of ophthalmology at U Penn. Two other similar trials began the same year. All the trials found that patients improved on tests of their vision within days of receiving the gene therapy. Follow-up studies of the same patients have reported stable gains in vision for at least 1-3 years.

LCA is an inherited disease that causes vision loss in early childhood. In about 10 percent of cases, LCA is caused by mutations in the gene RPE65, which makes a protein needed in the retina—the light-sensitive tissue in the eye. The retina contains millions of photoreceptors whose job it is to detect light and transform it into electrical signals that are ultimately sent to the brain. Without RPE65—which is made in cells under the retina— the photoreceptors aren’t able to recharge their light sensitivity. They also become sickly and die off over time, which ultimately leads to blindness.

The U Penn group’s gene therapy approach involves packaging a normal RPE65 gene into a small virus called the adeno-associated virus, which isn’t known to cause any human diseases. The virus is injected underneath the retina and delivers the gene where it’s needed.

The current study followed 10 LCA patients from Dr. Bennett’s phase I clinical trial, which is taking place at the Children’s Hospital of Philadelphia. The patients had received injections in their worse-seeing eye, toward the upper and outermost edge of the retina, which connects to the brain on the same side.

The researchers found that brain pathways from the treated eye were similar to those of normally-sighted people. But the brain pathways from the untreated eye had thinned. The thinning was correlated with age, suggesting that it became worse over time as a result of disuse of the untreated eye. Meanwhile, the visual pathways from the treated eye showed improvement with time after treatment.

Finally, the researchers correlated these structural changes with clinical measures. With greater regeneration of visual pathways, there was less nystagmus—an involuntary side-to-side flickering movement of the eyes. Also, using functional MRI (fMRI), the authors found higher levels of activity in the area of visual cortex receiving input from the treated eye.

“It’s an elegant demonstration that these visual processing pathways can be restored even long after the period when it was thought there would be a loss of plasticity,” Bennett said in a statement from U Penn. She and her co-authors said that a forward-looking study, in which patients could undergo brain imaging before and after receiving gene therapy, would further shed light on the time course of changes in the brain due to retinal gene therapy.

- By Daniel Stimson, Ph.D.

Reference: Ashtari et al. Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis. Science Translational Medicine, July 2015.