Developing Gene-Specific Molecular Approaches to Treat Inherited Retinal Diseases

First FDA approval marks beginning of new era

Historically, the only treatments available for inherited retinal diseases (IRDs) were approaches that slowed rather than reversed disease progression. In late 2017, however, the FDA approved voretigene neparvovec—the first gene therapy approved in the United States for the treatment of a genetic disease—paving the way for a new era of IRD treatments.

One of the primary obstacles to developing IRD treatments has been the lack of understanding of the genetic etiology of these conditions and the kinetics of disease progression specific to each gene, says Alessandro Iannaccone, MD, MS, director of Duke’s Center for Retinal Degenerations and Ophthalmic Genetic Diseases. Now that researchers have identified the causes for most IRDs and are starting to understand the kinetics and molecular mechanisms of some IRDs, more targeted approaches to treatment are being developed and tested.

“Years of laboratory work and convincing proof of principle studies have shown that gene therapy is an option for these disorders,” Iannaccone says. “It’s exciting that now we’re at the implementation phase for a number of these therapies.”

Duke is involved in several new trials:  

  1. Safety and efficacy of rAAV-hRS1 in patients with X-linked retinoschisis. This phase 1/2, multicenter clinical trial is evaluating the safety and efficacy of intravitreal injection of an adenovirus-associated virus (AAV) vector expressing retinoschisin. Enrollment is complete for adults and is being completed for pediatric patients, and collection of one-year data is planned for between April and May 2019. A phase 2b/3 trial is anticipated.
  2. Safety and efficacy of rAAV2tYF-GRK1-RPGR in subjects with X-linked retinitis pigmentosa caused by RPGR-ORF15 mutations. This multicenter, phase 1/2, dose escalation study will assess the safety and efficacy of subretinal injections of an AAV vector expressing RPGR in patients with a mutation in open reading frame 15 (ORF15). A clinical observational study is being run in parallel with patients who do not qualify for the phase 1/2 trial to better understand disease kinetics and mechanisms and identify a well-characterized group of patients with RPGR-ORF15 who could qualify for a subsequent trial once the intervention’s safety has been confirmed.
  3. RST-001 phase 1/2 trial for advanced retinitis pigmentosa. This multicenter dose escalation study is assessing the safety and efficacy of intravitreal injection of RST-001, which uses channelrhodopsin to confer light sensitivity to retinal ganglion cells—an approach that combines gene therapy with optogenetics.

These trials are just the beginning, Iannaccone says. Given the heterogeneity of IRDs—more than 300 genes are involved—many more treatments are needed. He anticipates that approval of the first few therapies will lead more companies to fund research and develop treatments, enabling clinicians to deliver treatments to a wider range of patients.

In the meantime, Iannaccone says, researchers will continue to study treatments that aren’t gene specific. “The new therapies are extremely exciting,” he notes. “But not everyone is going to be immediately treatable with these gene-specific approaches, so, at the same time, we still need to be looking for ways to provide across-the-board benefit and slow down progression while we wait for these other treatments.”

To learn more about the trials, please contact Amy Clark, PhD, clinical research coordinator at the Duke Eye Center, at 919-684-8798 or