Gene therapy helps several blind people see better
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.”
Technique controversial
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.
Two weeks after the injections, all three patients reported improved vision in the injected eyes, Maguire said. By gauging pupillary response to light -- researchers’ only objective measure of vision -- they found that light sensitivity had improved about threefold. The treatment also reduced nystagmus, an uncontrollable roaming of the eye common in blind people.
The patients also performed better on more subjective tests. One patient’s vision on an eye chart, for example, improved from 20/640 to 20/290, about 3 1/2 chart lines better, according to Dr. Jean Bennett, lead author of the study. The Food and Drug Administration requires three lines of improvement to consider a treatment effective.
No ill effects found
The therapy did not produce inflammation in the eye or any other toxic side effects, the researchers said. One patient did develop a small hole in the retina that they suspect was a result of the surgery, but it did not interfere with vision.
“All three subjects are asking if they can have their other eye injected,” High said. “That’s a pretty good indicator of its effectiveness.” The current research protocol does not allow for that, however.
The researchers have no idea how long the improvements will persist, but dogs given the treatment have remained stable for at least eight years, she said.
The British group also treated three patients, using slightly smaller doses of the vector. They also found no ill effects. Their patients did not have improved visual acuity, but one of them, 18-year-old Steven Howarth, had improved light sensitivity, especially at night.
“My sight when it’s getting dark or it’s badly lit is definitely better,” he said in a statement. “It’s a small change -- but it makes a big difference to me.”
Howarth is “staying out later and more confident at night,” Ali said.
Both groups are now increasing the vector dosage and moving toward younger children whose visual apparatus is less deteriorated. Ideally, High said, the treatment would start when the disorder was diagnosed in children.
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