Leber's congenital amaurosis experience a model for other inherited eye diseases, speaker says

Key Points

New Orleans-The discovery of genes associated with Leber congenital amaurosis (LCA) is "a great success story for ophthalmology," and the steps taken in search of a cure for the disorder can serve as a model for other inherited eye diseases, said Edwin M. Stone, MD, PhD, in the 64th Jackson Memorial Lecture during the opening session of the annual meeting of the American Academy of Ophthalmology (AAO).

"I think it's really exciting that human trials of gene replacement therapy have begun in our country and in the United Kingdom, and now that they have, it's really important for all of us to be on the lookout for individuals affected with this disease and to arrange genetic testing for them," said Dr. Stone, director of the Carver Family Center for Macular Degeneration and the Carver Nonprofit Genetic Testing Laboratory, University of Iowa, Iowa City, which offers tests for several eye disorders. "Of course, the genetic revolution in ophthalmology is much broader than LCA. Scores of genes that cause eye disease have been discovered in the past 15 years, and the time has come for every ophthalmologist to begin taking advantage of these discoveries to help patients."

In the past 11 years, he said, nine groups of researchers have identified 11 different genes responsible for about 70% of LCA cases.

Additionally, some patients with mutations of the CR± gene have periarteriolar preservation of the retinal pigment epithelium (RPE) visible via fundus photography, he added. Dr. Stone also is the holder of the Seamans-Hauser Chair in Molecular Ophthalmology at the University of Iowa and is the only practicing ophthalmologist who receives funding as a Howard Hughes Medical Institute investigator.

Developing treatments

As an example of what already has been accomplished in the development of a treatment for LCA, Dr. Stone described the case of a 3-year-old boy with a homozygous stop mutation in the gene RPE65.

The child's vision had been very poor since birth, and he had nystagmus. The electroretinogram was nonrecordable.

"When you dilate this child's eyes and look in with an ophthalmoscope, it's very surprising how normal everything looks. There's a very healthy-appearing optic nerve, the vasculature is essentially normal, the RPE looks healthy. There's really no structural explanation for this child's extremely poor vision," he said. "These are the clinical findings that are typical of LCA."

In 1997, Marlhens and co-workers showed that the RPE65 gene caused LCA, Dr. Stone said, and Aguirre, et al., characterized a canine model of the disease in 1998. Acland and colleagues successfully treated the model by using adeno-associated virus-mediated gene replacement in 2001, and Jin and co-workers found that the RPE65 gene was the long-sought retinoid isomerase of the visual cycle in 2005.