Investigational gene therapy for Leber's congenital amaurosis improved vision in two separate clinical trials

FORT LAUDERDALE, Fla. — Gene transfer therapy has successfully halted retinal degeneration and improved visual acuity in young adults with Leber's congenital amaurosis, two separate groups of clinical investigators announced during the Association for Research in Vision and Ophthalmology meeting here.

Both researchers' findings were published online Sunday in the New England Journal of Medicine. Both studies represent the first successful application of gene therapy in human patients for the debilitating retinal condition.

One group, led by researchers from the University of Pennsylvania and the Second University of Naples, Italy, outlined its results at a press conference here. The other group, led by researchers from the Moorfields Eye Hospital in London, presented its findings at a symposium during the meeting.

"We consider this a stepping stone to a new age, where the same strategies and the same agents can be used to treat conditions that are far more prevalent," Jean Bennett, MD, PhD, of the University of Pennsylvania, said. "An example would be Stargardt's disease."

Dr. Bennett was joined at the press conference by Katherine A. High, MD, and by phone by her husband, Albert M. Maguire, MD, and Alberto Auricchio, MD, from Italy.

In both studies, patients were injected with a normal version of the gene RPE65, a retinal pigment epithelium-specific protein, which is mutated in patients with one form of Leber's congenital amaurosis.

In the University of Pennsylvania-led trial, three patients were enrolled: one 19-year-old woman and a set of 26-year-old twins, male and female, under the supervision of Francesca Simonelli, MD, from the Second University of Naples. They each received the therapy between October and January at the Children's Hospital of Philadelphia and were followed for 6 months.

These investigators reported that patients were able to read 3.5 lines after a single injection, whereas at baseline they were limited to hand motion perception. Researchers also reported that the injected eye became about three times more sensitive to light. One patient showed improvement in navigating an obstacle course, and all three had reduced signs of nystagmus.

"After injecting the study agent into one eye, we evaluated a number of systemic and ocular findings to look for toxicity," Dr. Maguire said. He noted that the researchers used stringent objective and subjective criteria to eliminate any uncertainty over the validity of the results.

Regarding adverse effects, one patient developed a macular hole that did not appear to affect vision.

"It was thought it was related to surgery and not the vector, and a modification was made to prevent this in future procedures," Dr. Bennett said.

The researchers plan to follow the patients for 15 years over a prescribed series of time intervals, which will taper off to an annual follow-up after a year and a half. They have also injected one other subject and have lined up two more patients who are willing to undergo this treatment.

In the second group, from Moorfields Eye Hospital, James W.B. Bainbridge, PhD, FRCOphth, said visual results were promising, and there were no complications from surgery or any toxic effects. This study also looked at three adults who were between 17 and 23 years old.

In one patient, improvement of three lines was seen, but it was not clinically significant because improvement was also detected in the untreated eye, Dr. Bainbridge said. Yet one patient exhibited five times more retinal sensitivity 6 months after surgery, with no improvement in the untreated eye. Another patient demonstrated dramatic improvement in navigating a controlled spatial environment and reported feeling more confident while maneuvering it.

Dr. Bainbridge said the group is encouraged by its findings so far, and a trial is already beginning in children.

In light of the publicity that surrounded both of these studies here, some audience members called for caution when interpreting these results until it is conclusively established that the treatment has a direct anatomic effect on patients.