Gene Therapy: Hope in Restoring Vision

For the first time research has shown that gene therapy can restore some vision in patients with Leber's congenital amaurosis, a rare inherited disorder which prevents the retina from processing light. Leber's begins eroding eyesight at birth and leaves its victims almost typically blind by the time they reach their mid-to-late 20s.

Currently, with modern surgical techniques and advanced medications, doctors have been able to restore vision in many patients with cataracts and other eye ailments, but until now they have been unable to return any vision to a patient with such a degenerative disease as Leber's.

Leber's, which afflicts close to 10,000 people in the USA, and 1 in 50,000 globally, was the focus of two separate studies whose findings were published on line in the New England Journal of Medicine.

Researchers from the University of Pennsylvania (UP) along with the Second University of Naples (SUN), Italy, and the Moorfields Eye Hospital (MEH) in London, represent the first successful application of gene therapy in human patients for this debilitating retinal condition.

Dr. Jean Bennett, professor and gene therapy expert, with her husband Dr. Al Maguire, eye surgeon, an associate professor at UP, co-authored the findings for this study. The husband-and-wife team also developed the medical procedure, which used genetic engineering techniques to load the viruses with healthy versions of the rpe65 gene, the gene that is faulty in people with Leber's.

Each study involved what are known as adeno-associated viruses, popular among gene-therapy researchers because of their ability to deliver new genes to cells. Once the viruses are loaded, tens of billions of them are injected into the space behind the retina.

To prevent risk of side effects to both eyes and to allow for visual acuity comparison, only one eye was treated in each patient.

In the UP trial, under the supervision of Francesca Simonelli, MD, from the SUN, three patients were enrolled: one 19-year-old woman and a set of 26-year-old twins, male and female. Each patient received therapy between October and January at the Children's Hospital of Philadelphia with six months of follow up.

This research reported an increase of three times more light sensitivity, and the ability to read 3.5 lines after a single injection, whereas prior to treatment the patients were barely able to perceive hand motions. They also noted that one patient showed improvement and added confidence while navigating an obstacle course.

One patient developed a macular hole that did not appear to affect the vision, and Dr. Bennett said, "It was thought to be related to surgery and not the vector, and a modification was made to prevent this in future procedures."

In the second group, after studying three patients between 17 and 23 years of age, James W.B. Bainbridge, Ph.D., FRCOphth from MEH, said visual results were promising, and there were no complications from surgery or any toxic effects. In one patient, a three line improvement was seen, but it was not significant because improvement was also detected in the untreated eye, said Dr. Bainbridge. Yet six months after the surgery one patient exhibited five times more retinal sensitivity with no improvement in the untreated eye.

The researchers will follow the patients at prescribed intervals for 15 years, finally arriving at annual reports after a year and a half. To date, one other patient has been injected and two more subjects are willing to undergo this treatment.

The results were something short of miraculous; with only 3 of the 6 studied showing an increase in visual acuity and still labeled legally blind. But researchers said, to get any improvement at all during such an early phase of the research suggests that the approach has promise for people with gene-based forms of blindness.

"We're learning things as we go along," said Dr. Bennett, "We were not really going for a cure. But we do view it as a success in that their vision has improved. I'd call it a dramatic response."

Although promising, caution is called for when interpreting the results. The trials are small; with little comparison groups and the anatomic effects on patients are not conclusive. However both teams are encouraged by the findings so far and are planning to move ahead with tests in younger patients and at higher doses.