For the first time, researchers have used gene therapy to increase light sensitivity and improve vision in patients who were virtually blind, a finding that offers new hope to hundreds of thousands of patients with inherited forms of vision impairment.
Although the patients had a rare form of blindness called Leber's congenital amaurosis, researchers believe the approach can ultimately be used for a broad spectrum of disorders, including retinitis pigmentosa and macular degeneration.
The experiments, so far meant only to prove the safety of the technique, produced "real clinical benefit" and "made a real difference in patients' lives," said geneticist Robin R. Ali of University College London, the senior author of one of two reports presented Sunday at a Fort Lauderdale, Fla., meeting of the Assn. for Research in Vision and Ophthalmology.
The reports were published online Sunday by the New England Journal of Medicine.
"The fact that they had patients who could now read lines on an eye chart . . . and one who could run an obstacle course -- this is a really great advance," said geneticist Stephen Rose, chief research officer of the Foundation Fighting Blindness, who was not involved in the research. "This has changed the landscape of hope for patients."
Added Dr. Morton F. Goldberg, an ophthalmologist at John Hopkins University's Wilmer Eye Institute: "In the field of retinal dystrophies, this is, I believe, the most important therapeutic discovery" in four decades. "It's a landmark."
The results are particularly important because gene therapy, in which a defective gene is replaced with a good one, has been "a snakebitten field," with at least two subjects in other experiments dying and a few others developing cancer, said Dr. Albert M. Maguire of the University of Pennsylvania School of Medicine, lead author of the second report.
A handful of children with severe combined immunodeficiency disease were successfully treated, but critics charged that conventional treatments would have been equally effective -- and safer. In France, three children treated for the disease developed leukemia because the delivery agent inserted the new gene in the wrong place.
Researchers have reported modest benefits for Parkinson's disease, but no gene therapy results have been as dramatic as the Leber's findings.
"We have been working for years, and it has really been rough," Maguire said. "Here we finally have something in a curable disease that really seems to be working."
Leber's congenital amaurosis affects about 3,000 people in the United States and perhaps 130,000 worldwide. Sufferers are born with severely impaired vision that deteriorates until they are totally blind in childhood or adolescence. There has been no treatment for it.
What makes Leber's a good candidate for gene therapy is the fact that most of the visual apparatus, including the retina, is intact, at least at birth. Typically, the defective gene that produces Leber's is one of several in a pathway that produces chemicals for the eye to generate an electrical signal to the brain.
If that gene can be replaced before the visual apparatus deteriorates from lack of use, then vision can be restored, Maguire said.
Hope beyond Leber's
That basic strategy could be used to treat a variety of congenital retinal disorders. "With an aging population, one of the most serious problems that hinders old people is the loss of sight," said Dr. Katherine A. High of Children's Hospital of Philadelphia and a coauthor of one of the studies.
Retinitis pigmentosa -- the broad family of disorders that includes Leber's -- affects an estimated 100,000 Americans. Macular degeneration affects 1.25 million Americans, and the number is expected to grow to 3 million by 2020 as the population ages.
Those conditions are caused by other defective genes, but the treatment principle would be the same. Researchers would have to design a specific delivery vehicle, or vector, for each disorder bearing the proper gene.
In the latest experiments, both groups of researchers used a gene called RPE65 that is defective in many Leber's patients. Both groups also used as a vector a small adeno-associated virus that infects humans and other primates but is not known to cause disease. Its safety has been shown in various gene therapy experiments.
The Pennsylvania group's vector was developed by High; the British group used one produced by Targeted Genetics Corp. of Seattle.
The Pennsylvania group treated two 26-year-olds and a 19-year-old. Between October and January, Maguire injected a bit of the vector below the retina into each patient's worse-damaged eye.