Optimization and Validation of a Virtual Reality Orientation and Mobility Test for Inherited Retinal Degenerations.

Purpose: To optimize a virtual reality (VR) orientation and mobility (O&M) test of functional vision in patients with inherited retinal degenerations (IRDs). Methods: We developed an O&M test using commercially available VR hardware and custom-generated software. Normally sighted subjects (n = 20, ages = 14-67 years) and patients with IRDs (n = 29, ages = 15-63 years) participated. Individuals followed a dim red arrow path to a "course exit," while trying to identify nine obstacles adjacent to, or directly in their path. Dark-adapted subjects completed 35 randomly selected VR courses at increasing luminances, twice per luminance step, binocularly, and uni-ocularly. Performance was graded automatically by the software. Patients with IRD completed a modified Visual Function Questionnaire (VFQ). Results: Normally sighted subjects identified approximately 50% of the obstacles at the dimmest course luminance. Except for two patients with IRD with poor vision, all patients were able to complete the test, although they required brighter (by >2 log units) luminances to identify 50% of the obstacles. In a single-luminance screening test in which normal subjects detected at least eight of nine objects, most patients with IRD underperformed; their performance related to disease severity, as measured by visual acuity, kinetic visual field extent, and VFQ scores. Test-retest differences in object detection were similar to the differences between the two eyes (±2 SD = ±2 objects). Conclusions: This VR-O&M test was able to distinguish subjects with IRDs from normal subjects reliably and reproducibly. Translational Relevance: This easily implemented, flexible, and objectively scored VR-O&M test promises to become a useful tool to assess the impact that IRDs and their treatments have on functional vision.

A Virtual Reality Orientation and Mobility Test for Inherited Retinal Degenerations: Testing a Proof-of-Concept After Gene Therapy.

PURPOSE: To test the ability of a virtual reality (VR) orientation and mobility (O&M) protocol to serve a measure of functional vision for patients with inherited retinal degenerations (IRDs). METHODS: A VR-O&M protocol designed using a commercially available VR hardware was tested in normally sighted control subjects (n=7; ages 10-35yo; Average 22.5yo) and patients with RPE65-associated Leber Congenital Amaurosis (n=3; ages 7-18yo; Average 12.7yo), in two of them before and after gene therapy. Patients underwent perimetry and full-field sensitivity testing. VR-O&M parameters correlated with the visual dysfunction. RESULTS: Visual acuities in RPE65 patients were on average worse than 20/200, dark-adapted sensitivity losses >5 log units, and fields constricted between 20° and 40°. Before treatment, patients required ~1000-fold brighter environment to navigate, had at least x4 more collisions, and were slower both to orient and navigate compared to control subjects. Improvements in cone- (by 1-2 L.u.) and rod-mediated (by >4 L.u.) sensitivities post-treatment led to fewer collisions (at least by half) at ~100-fold dimmer luminances, and to x4 times faster navigation times. CONCLUSION: This study provides proof-of-concept data in support for the use of VR-O&M systems to quantify the impact that the visual dysfunction and improvement of vision following treatments has on functional vision in IRDs. The VR-O&M was useful in potentially challenging scenarios such as in pediatric patients with severe IRDs. TRANSLATIONAL RELEVANCE: A VR-O&M test will provide much needed flexibility, both in its deployment as well as in the possibility to test various attributes of vision that may be impacted by gene therapy in the setting of translational studies. PRECIS: This study provides proof-of-concept data in support for the use of a virtual reality orientation and mobility test to quantify the impact of the disease and of treatments thereof on functional vision in inherited retinal degenerations.

Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy.

Until recently, there was no approved treatment for a retinal degenerative disease. Subretinal injection of a recombinant adeno-associated virus (AAV) delivering the normal copy of the human RPE65 cDNA led to reversal of blindness first in animal models and then in humans. This led to the first US Food and Drug Administration (FDA)-approved gene therapy product for a genetic disease, voretigene neparvovec-rzyl (Luxturna). Luxturna was then approved by the European Medicines Association and is now available in the US through Spark Therapeutics and worldwide through Novartis. Not only has treatment with Luxturna changed the lives of people previously destined to live a life of blindness, but it has fueled interest in developing additional gene therapy reagents targeting numerous other genetic forms of inherited retinal disease. This review describes many of the considerations for administration of Luxturna and describes how lessons from experience with Luxturna could lead to additional gene-based treatments of blindness.