Gene therapy trials offer hope for inherited retinal diseases


Phase III study of RPE65 for Leber’s congenital amaurosis under way, among other research

TAKE HOME: A phase III trial of RPE65 gene therapy for Leber’s congenital amaurosis is under way. Phase I gene therapy trials for several other inherited retinal diseases are in progress or being planned.


By Cheryl Guttman Krader; Reviewed by Edwin M. Stone, MD, PhD

Iowa City, IA-Recent research progress provides reason for clinicians to assume an optimistic posture towards patients with inherited retinal diseases.

“It is hard to imagine all of the progress that has occurred in gene therapy research for inherited retinal diseases during the 5 years since the first human RPE65 gene therapy,” said Edwin M. Stone, MD, PhD, director of the Institute for Vision Research at the University of Iowa, Iowa City. “Now, multiple trials are under way, many others are planned, and this is really just the beginning.

“Furthermore, affordable genetic testing is available for the conditions being considered for future clinical trials,” he said. “Patients should be undergoing testing now to determine their genotype so that they will be ready to participate once trials begin recruitment.

 “In the future, we hope that gene therapy might also be used in a genetically-corrected cell replacement approach to help patients with advanced stages of disease, and we also need to think about electronic retinal prostheses that can allow people who have become completely blind from their inherited degenerative disease to function more effectively,” he added.

Gene replacement therapy

Reviewing the current status of gene replacement therapy trials for inherited retinal disorders, Dr. Stone noted that the phase I/II trials of adeno-associated virus (AAV)-mediated RPE65 gene replacement for Leber’s congenital amaurosis (LCA) are finishing up and a phase III trial is underway in Philadelphia and Iowa City. Additionally, numerous other trials are being organized to treat other forms of LCA and numerous other retinal degenerations.

“Sixteen genes account for more than 75% of patients with the clinical findings of LCA and molecular testing for these genes is excellent today,” Dr. Stone said.

He added that Project 3000 ( is a philanthropically funded project at the University of Iowa’s Carver Laboratory that can help defray the cost of genetic testing for LCA patients whose families are uninsured and cannot afford the cost. 

“Thanks in part to this project, it is estimated that fewer than 150 individuals with LCA in the United States who are under the age of 20 years have not yet had genetic testing,” Dr. Stone said.

Other gene therapy trials underway for inherited retinal diseases include a phase I trial of ABCA4A gene replacement therapy for Stargardt’s disease, which is being conducted at sites in Portland, OR, and Paris, France, and a phase I trial of MY07A gene therapy for Usher syndrome  in Portland.  In addition, a phase I trial of AAV-mediated CHM gene therapy for choroideremia is ongoing in Oxford, UK, and a gene therapy trial for patients with retinitis pigmentosa (RP) due to MERTK mutations was recently launched in Saudi Arabia.

“A trial of AAV-mediated gene transfer of the soluble VEGF receptor Flt-1 for treatment of exudative age-related macular degeneration is being conducted in Framingham, MA, and Perth, Australia,” Dr. Stone said. “While this therapy is not relevant to pediatric ophthalmology, it has huge potential importance for ophthalmology in general.”

Other studies of gene therapy in animal models that are being considered for future clinical trials include: X-linked retinoschisis; X-linked, autosomal recessive, and autosomal dominant RP; achromatopsia; Leber hereditary optic neuropathy, Bardet Biedl Syndrome, MAK associated RP and GUCY2D, RPGRIP1 and CEP290 associated LCA.

Cell replacement therapy

Ongoing research to develop patient-derived induced pluripotent stem cells to replace lost photoreceptors and RPE cells aims to help individuals with more advanced stages of inherited retinal diseases. In this approach, pluripotent stem cells are generated from autologous skin, then are induced to develop into retinal precursor cells. These cells may be transfected with a normal copy of the patient’s defective gene using the same types of gene therapy vectors currently being used in vivo in clinical trials.   

Research conducted at the University of Iowa provides proof of principle for this type of genetically-engineered cell replacement therapy [Tucker BA, et al. PLoS One 2011]. In this study performed in an immune-compromised retinal degenerative mouse model, pluripotent stem cells were derived from the skin of red fluorescent mice and induced to generate photoreceptor precursor cells.

The latter cells were then injected into the eyes of adult, nonfluorescent, rhodopsin null mice that had lost all of their photoreceptors. Follow-up testing confirmed that the injected cells differentiated into photoreceptors that made synaptic connections to the inner retina, resulting in restoration of electroretinal function.

Edwin M. Stone, MD, PhD

E: [email protected]

Dr. Stone has no financial interest in the subject matter. This article is based on Dr. Stone’s presentation during Pediatric Ophthalmology 2012 at the annual meeting of the American Academy of Ophthalmology.


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