Gene Therapy May Restore Vision in LCA

Laura Newman

September 15, 2011

September 15, 2011 — Gene therapy for Leber congenital amaurosis (LCA) is safe and effective, according to 3-year follow-up study results published online September 12 in the Archives of Ophthalmology.

LCA, a rare form of inherited eye disease, begins with severe visual impairment at birth, leads to progressive vision loss, and culminates in blindness. Three groups of investigators have tested the gene transfer technique, all showing that it is possible to correct a defect in the retinal pigment epithelium (RPE). Retinal deterioration is a hallmark of the disease.

The gene transfer technique applies to a variant of LCA called LCA2, which is caused by RPE65 gene mutations. RPE65 converts vitamin A into its usable form for vision. Investigators have described at least a dozen different variants of LCA, which together occur in about 1 of 8000 children.

"The most surprising finding was that patients with the worst vision did better," Samuel Jacobson, MD, the study's lead investigator and professor of ophthalmology at the University of Pennsylvania, Philadelphia, told Medscape Medical News.

In contrast, patients with improved foveal structure before treatment lost retinal thickness and acuity after subfoveal injections. As a result, they will avoid injections near the fovea and macula in the future.

Dr. Jacobson stressed that research in this area should proceed systematically. "This is the first study to show that we should avoid the fovea. It's important that we do good where we know it can be done, and that we avoid harm."

Putting the study in context, Dr. Jacobson said that his group has the longest follow-up and is the first to show a problem with injections near the fovea. In addition, the group tried to address many case selection and technique questions, "We need to do a little homework with the technique, which is not necessarily a proven treatment for all people with the disease."

Dr. Jacobson and coinvestigators evaluated the safety and efficacy of subretinal injections of adeno-associated virus carrying the RPE65 gene in 15 patients followed up for up to 3 years. The researchers evaluated 3 different injection strategies between ages 11 and 13 years. In each case, they administered injections on the worse-functioning eye.

The article provides an exhaustive clinical review of the 15 patients, providing a rich base for further study. Of 5 cohorts, the first 3 cohorts received single subretinal injections. Two of the cohorts comprised young adult patients between the ages of 20 and 30 years; cohort 3 comprised patients younger than age 18 years. Cohorts 4 and 5 had double injections, but less volume was used. After the injections, 13 of 15 patients absorbed the subretinal fluid within 48 hours and had no evidence of intraocular inflammation.

There was 1 postoperative retinal detachment, which was surgically repaired without further complication. Choroidal effusion and ocular hypotension occurred in the immediate postoperative period in 2 patients, and steroid-induced ocular hypertension occurred late in 1 patient. Systemic safety analysis revealed no clinically significant abnormalities after gene transfer. Of the various injection sites for the surgery, injecting near the fovea did not help with visual acuity.

Ultimately, Dr. Jacobson said, "We will want to hit the safest places on the left, right, and down below to make the world less dangerous and enhance mobility for these patients." Another trial is evaluating a 3-injection-site schema.

Dean Bok, PhD, director of the retinal cell biology laboratory at the Jules Stein Eye Institute at the University of California, Los Angeles, praised the trial, acknowledging that the study nonetheless is not a "game breaker." Research into gene replacement for this disorder has been flourishing in the field, with this article being the fourth or fifth clinical trial report.

Dr. Bok, who was not involved in the study, told Medscape Medical News that it was disappointing that the outcomes were poor near the fovea, but he added, "There may be better ways to deliver the virus, and directly to the cones as well."

The age at which to do this kind of work, with all its ethical and patient consent issues and other factors, remains controversial. Dr. Bok believes that the "younger the better," whereas Dr. Jacobson said that he has seen "patients age 25, 30, or 35 do remarkably well compared with young children, because the level of deterioration is quite variable." Dr. Bok also underscored that the gene technique was not restorative, but really gives people vision where they have not had it before.

Hendrik Scholl, MD, visiting professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News that the publication provides a "very comprehensive review of clinical data and long-term observations." He sees gene replacement therapy applications building for other eye diseases, such as Stargutt macular dystrophia, which causes central vision loss in young people between the ages of 6 and 20 years. Dr. Scholl, who was not involved in the study, said that he also sees a "role for more genotyping and getting a molecular diagnosis so that patients can get referred into clinical trials.

The field of gene therapy in ophthalmology is expanding. Although Dr. Jacobson was excited about these results, he sees much more work ahead, and plenty of room for other approaches. "We have not conquered central vision yet, and it is premature to drop this same technique onto the other eye." He also envisions a likely role for combination therapies, with many drug therapies on the horizon. Buoyed by results in LCA, there is a wealth of research with gene therapy in other ophthalmologic disorders.

The clinical trial was supported by the National Eye Institute. Dr. Jacobson works for the University of Pennsylvania, which together with the University of Florida, and Cornell University, holds a patent on the described gene therapy technology. Dr. Bok and Dr. Scholl have disclosed no relevant financial relationships.

Arch Ophthalmol. Published online September 12, 2011. Abstract


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