Gene Therapy Improves Vision in Second Eye of 3 Adults

Ricki Lewis, PhD

February 08, 2012

February 8, 2012 — Three adults whose vision improved after gene therapy for Leber congenital amaurosis type 2 (LCA2) in the worse eyes have progressed further after receiving gene therapy in their second eyes, according to a report published online February 8 in Science Translational Medicine.

LCA2 is 1 of at least 15 types of the disorder, which disrupts transmission of light to the retina, impairing vision in childhood and leading to total blindness. An autosomal recessive mutation in the RPE65 gene causes LCA2. The gene encodes an all-trans-retinyl ester isomerase essential to generate 11-cis-retinal, which is the form of vitamin A that photoreceptors use. The gene functions in the retinal pigment epithelium.

Left: Brain of a patient with LCA with brain response from visual stimuli the day before gene therapy. Right: Brain of the same patient with brain response from the same visual stimuli 90 days after gene therapy. [Image courtesy Manzar Ashtari, PhD, Children’s Hospital Philadelphia, Pennsylvania.]

Subretinal Injection of Gene in Viral Vector

The new study, by Jean Bennett, MD, PhD, from the F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, and the Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia, Pennsylvania, and colleagues, continues a phase 1/2 clinical trial that treated the worse eyes in 12 individuals, all of whom improved shortly after receiving 1.5 × 1010 to1.5 × 1011 adeno-associated virus (AAV) vectors via subretinal injection. Assessments included tests of full-field light sensitivity and pupillary light reflex, ability to navigate an obstacle course, and activation of the visual cortex observed with functional magnetic resonance imaging (fMRI).

The researchers performed gene therapy on the contralateral eyes of 3 of the initial 12 patients to assess immune response to the vector 1.7 to 3.3 years after initial treatment. "We did studies in animals using real test conditions and didn't see a toxic immune response. But a human is not equal to a mouse, which is not equal to a dog, which is not equal to a monkey. Readministration hasn't been done in humans. Fortunately, the immune response was benign," Dr. Bennett told Medscape Medical News.

A previous clinical trial with AAV gene therapy to treat hemophilia revealed an immune response. "Most humans, unlike the dogs in preclinical studies, are infected with AAV, so we have circulating antibodies and memory cells against the viral coat protein," explained Dean Bok, PhD, professor of ophthalmology at the Jules Stein Eye Institute of the David Geffen School of Medicine at the University of California, Los Angeles, in an interview with Medscape Medical News.

Surgeon Al Maguire, MD, introduced the gene-carrying viruses to areas of the retina bearing photoreceptors, based on imaging results. The patients had received escalating doses on their first eyes, but a higher dose (1.5 × 1011 vg in 300 μL fluid) for the second treatment.

In all 3 patients, vision improved, particularly for light sensitivity, with no adverse effects or migration of virus beyond the eye. Lead investigator Manzar Ashtari, PhD, from the Department of Radiology at the Children's Hospital of Philadelphia, told Medscape Medical News, "It was exciting to see how the brain responds. The eye is an extension of the brain, so if there's manipulation in the eye, the brain knows. The before-and-after fMRIs are like day and night. This is how these patients are."

In the future, Dr. Ashtari said, fMRI will play a bigger role in presurgical mapping of healthy photoreceptors, which can help in patient selection. The eyes of children with LCA2 usually have more extensive islands of photoreceptors than those of adults.

The patient who received the highest initial AAV dose improved to the greatest extent. Moreover, in all 3 patients, the first-treated eyes improved further after treatment of the second eyes; for example, decreasing the amplitude of nystagmus. Dr. Bennett speculated that this finding may reflect plasticity in the nervous system. "Vision includes many parameters, including depth perception and identification of edges and movement. These circuits may develop the best if both eyes are functioning at a certain level," she said to Medscape Medical News.

One patient improved in sensitivity to red, indicating involvement of cones. "Perhaps red sensitivity picked up because there are twice as many red cones as other colors in the human eye," said Dr. Ashtari.

The US Food and Drug Administration has yet to approve any gene therapy, and for LCA2 that will happen at least a year after completion of a phase 3 trial. However, the researchers are already developing a training program.

"Any retinal surgeon will be able to carry out the procedure, but since it's currently not standard of care, we have set up a plan including didactic material and hands-on training in a wet lab," said Dr. Bennett. Dr. Bok is optimistic. "Retinal surgeons are highly skilled at working in the subretinal space. Ophthalmologists around the world could readily perform it."

In addition to being safe and effective, the gene therapy appears to be long-lasting, said Dr. Ashtari.

John Chiang, PhD, director of the Casey Eye Institute Molecular Diagnostic Laboratory at Oregon Health Science University in Portland, noted that "Dr. Jean Bennett and her colleagues have once again demonstrated the great potential of gene therapy in the treatment of patients with LCA2. The same concept may be applied broadly to other forms of retinal degeneration."

Dr. Bennett and Dr. Maguire have a patent pending for gene therapy for LCA2 but waived financial interest in 2002. Dr. Bennett served on a scientific advisory board for sanofi-aventis in 2010 to 2011 and has consulted for GlaxoSmithKline. Two coauthors hold a patent on AAV vectors and are on the scientific advisory board of Avalanche Technologies, and one of these coauthors has consulted for Tacere Therapeutics, Genzyme, Novartis, and Genetix Inc. The other authors have disclosed no relevant financial relationships. Ricki Lewis is the author of The Forever Fix: Gene Therapy and the Boy Who Saved It, which is about the clinical trial described in the reported article.

Sci Transl Med. Published online February 8, 2012.