Tapping gene therapy potential for inherited retinal diseases


The gene therapy technology already exists to treat most inherited retinal disease. The current challenge is to drive down the costs of implementing the technology.

Reviewed by Edwin M. Stone, MD, PhD

Though gene therapy technology already exists to treat most inherited retinal disease, the current challenge is to drive down the costs of implementing the technology-thus availing more patients with the benefits of treatments and possibly prevent inevitable visual deterioration.

Edwin M. Stone, MD, PhD, recounted the case of a 14-year-old boy with an inherited eye disease who was born deaf and received bilateral cochlear implants during the first years of his life. The boy’s visual acuity levels were 20/25 and 20/32 in the right and left eyes, respectively. Despite good visual acuity, more recently, he had been having difficulty seeing in dim light.

A Goldmann perimetry evaluation showed normal responses to large, bright stimuli. However, there was some restriction at the 12e and 14e isopters, explained Dr. Stone, director, Stephen A. Wynn Institute for Vision Research, and professor, Department of Ophthalmology and Vision Sciences, University of Iowa, Iowa City.

A fundus examination showed that both discs were normal and the vessels were slightly constricted. Some pigmentation was present in the midperipheral retina.

Based on these findings, deafness at birth, and retinitis pigmentosa at the beginning of the second decade of life, the patient was given a diagnosis of type I Usher syndrome. Molecular testing showed the presence of the two most common mutations in the USH1C gene, i.e., Val72Val (a splice variant) and Thr78insC.

Treatment and management



Treatment and management

Dr. Stone described a treatment currently in development that will involve a subretinal injection of about 300 μl of a clinical-grade virus containing a normal USH1C gene. The treatment will be delivered to the region of the fundus most likely to be affected within a few years, and one that is unlikely to cause much harm should the treatment prove to be worse than the natural history of the disease.

After treatment, patients will be followed for several years to identify differences between mirror-image regions in the treated and untreated eyes using Goldmann perimetry and optical coherence tomography.


Status of gene therapy

Currently, Dr. Stone noted, only seven retinal genes were or are being studied as potential gene therapies in humans with retinal diseases: ABCA4, CHM, RS1, MYO7A, RPE65, MERTK, and ND4.

Dr. Stone and colleagues wanted to determine how often an affected gene is identified but no treatment trial is available. The investigators studied 1,000 consecutive families with Mendelian retinal disease in their clinic. They found disease-causing genotypes in 76% of the families at an average cost of $980 per family.

“The 760 genotypes that were discovered in the 1,000 families were distributed among 104 different disease-causing genes, some of which were rarer than others,” Dr. Stone said. “Ninety-one of the genes caused disease in less than 1% of this large cohort and USH1C was one of them.”

The take-home message today, however, is that the technology already exists to develop a treatment for most of the inherited retinal diseases, and more than 75% of the genes will fit into an adeno-associated virus vector, Dr. Stone said.

“We just need to find a way to deploy this technology at a lower cost and in a higher throughput manner than we have been doing,” he said.

Dr. Stone and colleagues are doing just that with the non-profit Steven W. Dezii Translational Vision Research Facility at the University of Iowa, where they can manufacture clinical-grade virus and transplantable retinal cells. Blueprints, instrument lists, protocols, and operating procedures are available to nonprofit groups interested in such an endeavor.



Edwin M. Stone, MD, PhD

E: edwin-stone@uiowa.edu

This article was adapted from Dr. Stone's presentation during Pediatric Subspecialty Day at the 2016 meeting of the American Academy of Ophthalmology. Dr. Stone has no financial interest in any aspect of this report. Project Usher (www.projectusher.org), a philanthropic program, provides molecular testing for patients with the clinical diagnosis of Usher syndrome who cannot afford it otherwise.

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