Adults with a genetic form of childhood-onset blindness experienced a remarkable recovery in night vision within days of receiving experimental gene therapy, according to researchers at the Scheie Eye Institute at the Perelman School of Medicine at the University of Pennsylvania.
The patients suffered from Leber’s congenital amaurosis (LCA), a congenital blindness caused by mutations in the gene GUCY2D. The researchers whose findings are reported in the journal iscience, delivered AAV gene therapy, carrying the DNA of the healthy version of the gene, into the retina of one eye for each of the patients, according to the clinical trial protocol. Within days of treatment, each patient showed large increases in visual functions mediated by rod-type photoreceptor cells in the treated eye. Rod cells are extremely sensitive to light and account for most of the human ability to see in dim light.
“These exciting results show that the basic molecular machinery of phototransduction remains largely intact in some cases of LCA and therefore may be amenable to gene therapy even after decades of blindness,” said the study’s lead author Samuel G. Jacobson, MD, PhDProfessor of Ophthalmology at Penn.
LCA is one of the most common congenital blindness diseases, affecting approximately one in 40,000 newborns. The degree of vision loss can vary from one LCA patient to another, but all of these patients have severe visual impairment from the first months of life. There are more than two dozen genes whose dysfunction can cause LCA.
Up to 20 percent of LCA cases are caused by mutations in GUCY2D, a gene that encodes a key protein needed in retinal photoreceptor cells for the ‘phototransduction cascade’ – the process that converts light into neuronal signals. Previous imaging studies have shown that patients with this form of LCA tend to have relatively preserved photoreceptor cells, particularly in rod-rich areas, suggesting that if functional, rod-based phototransduction could be restored GUCY2D were present. Early results with low doses of gene therapy reported last year were consistent with this idea.
The researchers used higher doses of gene therapy in two patients, a 19-year-old man and a 32-year-old woman, who had particularly severe rod-based vision problems. In daylight, the patients had some, albeit severely reduced, visual function, but at night they were virtually blind, with photosensitivity on the order of 10,000 to 100,000 times less than normal.
The researchers gave the therapy to only one eye in each patient, so the treated eye could be compared to the untreated eye to measure treatment effects. The retinal surgery was performed by Dr. Allen C. Ho, Professor of Ophthalmology at Thomas Jefferson University and Wills Eye Hospital. Tests showed that in both patients, the treated eyes became a thousand times more sensitive to light in low light conditions, significantly correcting the original vision deficits. The researchers used a total of nine complementary methods to measure the patients’ light sensitivity and functional vision. These included a test of room navigation skills in low light and a test of students’ involuntary responses to light. The tests consistently showed significant improvements in rod-based low-light vision, and patients also noted functional improvements in their daily lives, such as: e.g. “can [now] recognize objects and people in the dark.”
“Equally striking was the speed of improvement after the therapy. Within eight days, both patients were already showing measurable efficacy,” said the study co-author Artur V. Cideciyan, PhDa research professor of ophthalmology at Penn.
For the researchers, the results confirm this GUCY2D Gene therapy to restore rod-based photoreceptor functions — and propose that GUCY2D-LCA patients with more severe rod-based dysfunction are likely to benefit most dramatically from therapy. The practical message is that when screening LCA candidates and monitoring them during a treatment study, emphasis should be placed on visual stick measurements.
The findings, the researchers say, also underscore the remarkable fact that in some patients with severe congenital vision loss, the retinal cell networks that mediate vision remain largely alive and intact, requiring only replenishment of a missing protein to start working again. more or less immediately.
Relation:
Jacobson SG, Cideciyan AV, Ho AC, et al. Restoration of night vision within days after decades of congenital blindness. iscience. Published online October 4, 2022: 105274. doi:10.1016/j.isci.2022.105274
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