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Scientists Refine Gene Therapy for Rare Congenital Blindness


In 2008, an NEI-supported research group reported that gene transfer therapy improved vision in three young adults blinded by Leber congenital amaurosis (LCA), a rare genetic disorder. In September 2011, NEI-grantees Samuel G. Jacobson, M.D., Ph.D., et al., reported all three participants remained healthy 3 years after treatment and maintained visual gains.1 The report also summarized lessons learned in the treatment of an additional 12 patients.

LCA is caused by mutations in any one of 17 different genes expressed in the light-sensing tissue layer in the back of the eye called the retina. One form of LCA results from mutations in RPE65, a gene that codes for a protein that, when functioning properly, participates in a process that allows photoreceptor cells in the retina to capture light and convert it into signals the brain perceives as images. RPE65 mutations inhibit this process, called phototransduction, resulting in early and severe vision loss. Although LCA greatly reduces the retinaís ability to capture light, the disease leaves the retina otherwise functional for some period of time before photoreceptors degenerate.

The goal of gene transfer therapy is to treat genetic diseases that result from missing or mutated genes. In the case of LCA gene transfer therapy, researchers used an adeno-associated virus (AAV) as a vector to insert a normal copy of the RPE65 gene into the retinal pigment epithelium (RPE), the retinal cell layer that expresses the RPE65 protein. AAV is a common virus that doesnít cause illness, making it an excellent vector to package genes for transfection into host cells.

The first three study participants, all in their early twenties, received an injection of genetically modified RPE65-AAV vector in select areas of the RPE beneath the retina. Within weeks of injecting AAV vector subretinally, the vision in all three initial participantsí treated eye improved, indicating successful transfection of the RPE65 gene. Although most participants did not experience gains in visual acuity-the ability to read letters on a chart-vision was brighter. Day vision sensitivity improved 50 fold; while night vision sensitivity improved 63,000 fold. Importantly, there were no adverse events related to the viral vector.


Based on the encouraging results in 2008, the researchers endeavored to improve the technique by evaluating several variables, including increasing the viral vector dose by administering two subretinal injections in different areas of the retina, injecting vector beneath the photoreceptor-rich area of the retina called the fovea, and treating younger patients with presumably less loss of photoreceptors.

To date, all 15 participants experienced modest visual improvements with no complications related to the AAV vector. Two participants achieved clinically significant gains in visual acuity, defined as the ability to read an additional 3 lines (15 letters) or more on an eye chart.

An additional injection safely expanded the amount of retina exposed to the RPE65-AAV vector. Visual field sensitivity testing allowed researchers to detect changes in the sensitivity of specific photoreceptors. Compared to readings taken before gene transfer therapy, the sensitivity of photoreceptors near injection sites increased after treatment.

The scientists were unable to demonstrate that injecting vector subfoveally consistently improved outcome, when compared to injecting vector into other parts of the retina. When measured with optical coherence tomography, a noninvasive technique used to examine retinal structure, some participants who received subfoveal injections experienced foveal thinning, which suggested a loss of photoreceptors.

Younger participants, when compared to the older participants, did not experience greater visual improvements. In fact, the two participants with the greatest visual acuity gains were among the oldest in the study. The researchers speculated that the number and health of remaining photoreceptors matter more than patient age, as the rate of photoreceptor loss varies considerably among people with RPE65-deficient LCA. The finding suggests older patients with slower photoreceptor degeneration may be good candidates for the therapy.

Safety was the primary outcome of this trial and others testing gene transfer therapy in RPE65-deficient LCA patients. Therefore, a conservative approach was taken that limited treatment to the eye with poorer vision. In the future, the researchers plan to seek further visual gains by giving three injections of RPE65-AAV vector and treating a patientís better eye.

Public Impact Statement/Significance:

Gene transfer therapy is safe and effective in restoring some vision in people with RPE65-deficient LCA, a disease recently considered untreatable. Data from the study suggest the therapy may help patients previously assumed too old to benefit and provides insight into gene transfer therapies for other retinal degenerative diseases.

Grant support:

U.S. National Institutes of Health, National Eye Institute (Clinical Trials of Gene Therapy for Leber Congenital Amaurosis U10EY017280-01). Identifier:



Gene Therapy for Leber Congenital Amaurosis


Last Reviewed: October 2011

Department of Health and Human Services NIH, the National Institutes of Health