Future data from other participants with LCA enrolled in the phase 1/2 study will be announced at a later date.
Two patients, a 19-year-old man and a 32-year-old woman, with GUCY2D-Leber congenital amaurosis (LCA) had a recovery of night vision after treatment with AAV5-GUCY2D gene therapy, according to data from a phase 1/2 study (NCT03920007) conducted at the University of Pennsylvania published in iScience.1
“These exciting results demonstrate that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA, and thus can be amenable to gene therapy even after decades of blindness,” study lead author Samuel G. Jacobson, MD, PhD, professor of Ophthalmology,University of Pennsylvania, said in a statement.2
Jacobson and colleagues found that these patients had increases in light sensitivity as measured by full-field sensitivity test (FST) from baseline in treated eyes, with no changes in untreated eyes.1 Patient 1 had a 2 lu increase in rod-mediated sensitivity at day 8, which increased to a 4.6 lu increase by 2 months. Patient 2 had a detectable increase in rod-mediated sensitivity at day 8, which increased to a 3.1 lu increase at 3 months, nearing 0.6 lu of the lower bound of normal. Using chromatic perimetry and retina-tracking perimetry, investigators confirmed that both patients had increases in visual field and more mixed- or rod-mediated sensitivity.
Visual acuity was also assessed via logMAR and neither patient experienced much change in acuity between treated and untreated eyes. However, low-luminance visual acuity (LLVA) greatly improved in both patients, with patient 1 improving by 45 letters (0.9 log) and patient 2 improving by 18 letters (0.36 log) in their treated eyes, while control eyes slightly improved by up to 8 letters (0.16 log). Investigators concluded that LLVA improvements were driven by large sensitivity improvements in the rod system of study eyes.
Investigators also found that average pupillary response improved from 0.13 and +0.01 log scot-cd.m-2 to -3.71 and -1.65 log scot-cd.m-2 in treated eyes of patients 1 and 2, respectively, while control eyes remained the same. They determined that outer nuclear layer (ONL) thickness and deep outer retinal structure and rod outer segment (ROS) thickness measurements were normal in the 2 patients prior to treatment, suggesting rod photoreceptor integrity in these regions and that structure and function may be separate in GUCY2D-LCA.
“Just as striking was the rapidity of the improvement following therapy. Within eight days, both patients were already showing measurable efficacy,” study co-author Artur V. Cideciyan, PhD, research professor of Ophthalmology, Penn added.2
Overall, Jacobson and colleagues concluded that gene therapy can greatly improve rod vision in patients with GUCY2D-LCA.1 They found further evidence to support that rod components remain intact in these patients even after decades of disuse, enabling restoration of function by gene therapy. They stressed that there should be an emphasis on rod vision measurements at screening of trials and enhanced monitoring throughout to accurately measure changes. They did note that the study was limited due to rarity of disease. Enrollment has completed in the ongoing trial and data from other patients will be reported in the future.