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Blindness Gene Therapy in Second Eye Shown Safe in Animal Studies

Gene therapy for a severe inherited blindness disorder (Leber's congenital amaurosis or LCA), which produced dramatic improvements last year in twelve children and young adults who received the treatment in a clinical trial, has cleared another hurdle. The same research team that conducted the human trial has now reported that a study in large animals has shown that a second injection of the normal gene (RPE65) into the opposite, previously untreated, eye is safe and effective, with no signs of interference from unwanted immune reactions following the earlier injection. LCA is an autosomal recessive retinal disease that progresses to total blindness by adulthood and that can be caused by mutation in any one of a variety of different genes, including the RPE65 gene. Approximately 3,000 people in the United States are estimated to have the disease. In the current study, the research team found no evidence of toxic side effects in the blood or the eyes of the ten animals—six dogs and four monkeys—that received the gene therapy (with the normal RPE65 gene). Each animal received an injection first in the right eye, then in the left eye 14 days later. All six dogs, which had been specially bred to have congenital blindness, had improved vision, in addition to showing no toxic effects from the gene therapy. The monkeys, which were not blind, also showed no toxic effects from the therapy. These new findings suggest that LCA patients who benefit from gene therapy in one eye may experience similar benefits from treatment in the other eye. Researchers had exercised caution by treating only one eye in the human trial. "We designed this study to investigate the immunological consequences of administering the gene therapy injection to the second eye after treating the first one," said senior author Dr. Jean Bennett, from the University of Pennsylvania School of Medicine. "The good news is that in animals, the second injection, like the first, is benign."

As in the human trials of this gene therapy, the researchers packaged a normal version of the gene that is missing in LCA inside a genetically engineered vector, adeno-associated virus (AAV). The vector delivers the gene to cells in the retina, where the gene produces an enzyme that restores light receptors. Although the virus used does not cause human disease, it had previously set off an immune response that cut short the initial benefits of gene therapy, notably in a 2002 human trial of gene therapy for the bleeding disorder hemophilia.

"Our current study in large animals provides encouraging indications that immune responses will not interfere with human gene therapy in both eyes," said co-author Dr. Katherine A. High, a pioneer in gene therapy who helped lead the hemophilia trial. "Like humans, monkeys generate neutralizing antibodies against both naturally occurring and injected AAV, but these antibodies did not prevent the injected gene from producing the desired enzyme." Dr. High is director of the Center for Cellular and Molecular Therapeutics at Children's Hospital of Philadelphia, which manufactured the vector used in the current study and the previous human trial for LCA.

In addition, the results may set the stage for gene therapy in LCA patients who were excluded from the previous trial. Adopting a conservative approach, the researchers did not treat LCA patients who already had neutralizing antibodies against AAV in their blood. As many as a quarter of all people may carry these antibodies by their teenage and young adult years. Fortunately, unlike other organs, both human and animal eyes are insulated from these circulating antibodies. (Co-author Dr. Stephen Orlin led studies of human samples and showed that even when antibodies to AAV were at high levels in the blood, antibodies within the eye remained at or near background levels.) The authors conclude that the presence of those antibodies in the blood will most likely not prevent effective gene transfer in human eyes.

This new LCA research served as the cover story of the March 3, 2010 issue of Science Translational Medicine. [Press release] [Science Translational Medicine abstract]