Second Dose of Gene Therapy Safe in Animal Studies
Using gene therapy that produced dramatic restoration of eyesight in 12 children and young adults who were treated in one eye for a severe inherited blindness, investigators have shown in an animal study that a second injection of genes into the opposite, previously untreated eye is safe and effective. These findings suggest that patients who benefit from gene therapy for Leber’s congenital amaurosis (LCA), a retinal disease that progresses to total blindness by adulthood, may experience similar benefits from treatment in the other eye.
Led by director of the Center for Cellular and Molecular Therapeutics, Katherine High, MD, HHMI, and her colleagues at the University of Pennsylvania, the research team treated 10 animals with a normal version of the gene missing in LCA packaged 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 does not cause human disease, it previously set off an immune response that cut short the initial benefits of gene therapy. Researchers who conducted the human trial for LCA exercised caution by treating only one eye.
The team found no evidence of toxic side effects in the blood or the eyes of the animals — four monkeys and six dogs — that received the gene therapy by injection in the right eye and 14 days later by injection in the left eye. All six dogs, bred to have congenital blindness, had improved vision in addition to showing no toxic effects. Monkeys, like humans, generate neutralizing antibodies against AAV; however, these antibodies did not prevent the injected gene from producing the desired enzyme. These results provide encouraging indications that immune responses will not interfere with human gene therapy in both eyes and that patients with antibodies against AAV in their blood, excluded from the initial human gene therapy trial, may be candidates for this treatment.
Subjects from the human trial, all of whom experienced partially restored eyesight in their treated eyes, were eager to receive the same treatment in the other eye. This animal study, published in Science Translational Medicine, advances that possibility. The research team is planning a new clinical trial of LCA therapy, which may include some of the subjects from the first group.