Barbara Boughton

October 26, 2009

October 26, 2009 (San Francisco, California) — In a dramatic phase 1 trial, gene therapy improved eyesight in people with one of the most severe forms of retinal degeneration, Leber's congenital amaurosis (LCA), and the improvements remained stable after 2 years of follow-up.

Changes in visual acuity and light sensitivity were most marked in children, who showed striking improvement in the ability to navigate a low-light obstacle course, according to researchers here at the American Academy of Ophthalmology Joint Annual Meeting With the Pan-American Association of Ophthalmology. The results of the phase 1 trial were also published online October 23 in The Lancet.

"We found efficacy in all subjects, but the most improvement in visual acuity and light sensitivity occurred in younger individuals," said senior researcher Jean Bennett, MD, PhD, who is the FM Kirby Professor of Ophthalmology at the University of Pennsylvania School of Medicine in Philadelphia, during an interview with Medscape Pathology and Lab Medicine. "The data are very encouraging and may jump start attempts to treat other inherited forms of blindness with gene therapy."

The 12 subjects in the trial ranged in age from 8 to 44 years, and 4 were between 8 and 11 years — the youngest individuals to receive gene therapy for a nonlethal disease. Although the patients did not regain normal eyesight, half of them improved enough so that they were no longer classified as legally blind.

LCA is marked by severe loss of vision and nystagmus that begins in early infancy and childhood and progresses to blindness by the third or fourth decade of life. The disorder is caused by mutations in any of 13 genes. Type 2 LCA, the form studied in the research trial, is caused by a mutation in the RPE65 gene, and accounts for about 6% of all cases.

In the study, a normal functioning RPE65 gene was spliced into a viral vector, and the vector was then injected into the subretinal space during surgery. "The modified virus piggybacks the healthy RPE65 gene into diseased cells and corrects the enzyme defect," explained lead author Albert Maguire, MD, associate professor of ophthalmology at Pennsylvania State University and a physician at the Children's Hospital of Philadelphia.

Drs. Maguire and Bennett and fellow researchers have been testing this approach with the RPE65 gene in LCA since 2000, when they first injected 3 dogs with the therapy. "A few months later they could see," Dr. Bennett said. "We became convinced that this would have a good chance for safety and efficacy in humans."

In May 2008, the research team published preliminary results of the phase 1 trial on 3 adults in the New England Journal of Medicine (2008;358:2240-2248), revealing that subjects showed improved function on vision tests. The trial was then extended to 9 other subjects, who received either a low, medium, or high dose of the therapy in the eye with the worst function at baseline.

Results indicated that all 12 patients reported improved vision in dimly lit environments beginning 2 weeks after surgery. Visual acuity improved significantly in 3 patients who received the low dose, 3 who received the medium dose, and 1 who received the high dose. In 1 patient, visual acuity worsened after treatment. However, visual field improved in all 12 patients, as did pupillary response and sensitivity to light. Seven had significant improvements in nystagmus. None experienced adverse events.

In an editorial accompanying The Lancet paper, Frans P.M. Cremers, PhD, and Rob W.J. Collin, PhD, from Radboud University Nijmegen Medical Centre in the Netherlands, noted that the study showed that "gene therapy might provide a major improvement of vision in patients with Leber's congenital amaurosis, and holds the promise that the progressive retinal degeneration in patients with retinitis pigmentosa can be slowed down or stopped, which would render the patients many more years of vision."

Indeed, the authors of the paper have already started preclinical studies of gene therapy in other inherited eye diseases, including retinitis pigmentosa and other forms of LCA. They will also be moving forward with a phase 3 trial, which they hope to complete in 2 years, with the goal of obtaining licensing from the US Food ad Drug Administration for the gene therapy treatment.

The current study conclusively shows that children with LCA and other inherited forms of retinal eye disorders are most likely to benefit from gene therapy because they have sustained less cellular damage than adults, said Tim Stout, MD, PhD, vice president of Oregon Health & Science University and professor at the Casey Eye Institute in Portland. Dr. Stout is heading a gene therapy trial treating patients with type 2 LCA, but using a different viral vector.

"We can all agree that treating patients earlier is probably a smart idea — at a stage where they can recover more visual function," he said. "We need to make sure this therapy is safe, but once we've done that, we can move toward treating younger and younger children, even children younger than 8 years old," he said.

Dr. Bennett, Dr. Maguire, Dr. Cremers, Dr. Collin, and Dr. Stout have disclosed no relevant financial relationships.

American Academy of Ophthalmology Joint Annual Meeting With the Pan-American Association of Ophthalmology (AAO-PAAO). Leber Congenital Amaurosis Therapy Update. Presented October 24, 2009.

Lancet. Published online October 23, 2009.


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