Solving the Leber's congenital amaurosis puzzle

October 1, 2010

A potential advance in the fight against blindness is the development of an experimental oral synthetic retinoid compound to treat two subtypes of Leber's congenital amaurosis.

Fort Lauderdale, FL-A potential advance in the fight against blindness is the development of an experimental oral synthetic retinoid compound (QLT091001, QLT Inc.) to treat two subtypes of Leber's congenital amaurosis (LCA).

The early results of an ongoing phase Ib study to test QLT091001 show visual function and behavioral changes in the first subjects treated with the drug, said Robert K. Koenekoop, MD, PhD, at the annual meeting of the Association for Research in Vision and Ophthalmology.

Now, "exciting progress is being made in what was thought to be an untreatable disease, and 15 genes responsible for LCA have been identified," said Dr. Koenekoop, director of the McGill Ocular Genetics Laboratory, and chief of the Pediatric Ophthalmology Division, Montreal Children's Hospital, McGill University Health Centre, Montreal.

"The genes control coding proteins in the retina with crucial functions, including ciliary transport, photoreceptor development, phototransduction, and the vitamin A cycle," he added. "All of these cycles are broken in LCA."

Following discovery of the LCA genes, Albert Maguire, MD, and Jean Bennett, MD, PhD, and colleagues at the University of Pennsylvania, developed a successful gene therapy for mutations in the RPE65 gene, which is one subtype of LCA, that first worked in dogs. In the animal studies, the dogs achieved functional vision after having been born blind. This therapy was later used successfully to improve vision in humans in early clinical trials.

"This was a huge achievement, especially in light of the fact that previous attempts at gene therapy in other diseases had not been helpful," Dr. Koenekoop said.

Research into LCA indicated that the retinoid cycle is broken in some forms of the disease as a result of mutations in some genes that block the vitamin A cycle, such that the end product, 11-cis-retinal, which is sensitive to light, is absent. Dr. Koenekoop explained that 11-cis-retinal cannot be administered as a drug because it is unstable.

The basis for using synthetic retinoids as replacement therapy for conditions where genetic defects result in deficiency of 11-cis-retinal is founded on experiments in mouse genetic models, including those developed in the laboratory of Krzysztof Palczewski, PhD. In these experiments, QLT091001, administered orally, worked rapidly to provide retinal function in mice, which was confirmed by electroretinography, pupillometry, and retinal cell counts. The effect was similar in dogs treated with QLT091001 injected into the eye.

Clinical studies

Based on the animal research, a safety study was done in healthy volunteers. One year later, three patients with LCA due to a genetic mutation in LRAT have been treated with oral QLT091001 in a phase Ib study.

"The preliminary results are very exciting," Dr. Koenekoop said. "The patients treated to date have achieved functional vision and there are positive behavioral changes in their lives."

Improvements were most pronounced in the youngest subject. This 10-year-old girl had very small visual fields, was legally blind, and walked with the assistance of a cane. One or two nights after she received the drug, she reported that she had developed a headache. Upon examination the following morning, she said that for the first time in her life she was able to walk downstairs unassisted. Shortly thereafter, she said her vision improved in low light.

"Her parents began to notice changes in her behavior," he said. "Four months after treatment, she refuses to carry a cane and can run."

Visual measurements correlate and corroborate her behavior, according to Dr. Koenekoop.