A new gene therapy method improves night vision in adults with congenital blindness, scientists suggest

University of Pennsylvania scientists' ground-breaking way to improve night vision in adults with congenital blindness will bring a spurt to ophthalmology: a gene therapy.

The novel method's results were published in iScience on September 4.

As UPenn stated, adults with a genetic form of childhood-onset blindness experienced striking recoveries of night vision within days of receiving experimental gene therapy, according to researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania.

The patients had Leber Congenital Amaurosis (LCA), congenital blindness caused by GUCY2D gene mutations. As per the clinical trial protocol, the researchers administered AAV gene therapy, which carries the DNA of the gene's healthy version, to the retina of one of the patient's eyes.

Each patient displayed significant gains in rod-type photoreceptor cell-mediated visual functions in the treated eye within days after treatment. The majority of the human eye's ability to see in low light comes from rod cells, which are incredibly light-sensitive.

“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,” said study lead author Samuel G. Jacobson, MD, Ph.D., a professor of Ophthalmology at Penn.

Almost 40,000 babies are affecting

One in every 40,000 newborns is born with LCA, which is one of the most common congenital blindness conditions, says UPenn.

The degree of vision loss varies from one LCA patient to the next, but all such patients have a severe visual disability from infancy.

LCA can be caused by the dysfunction of more than two dozen genes.

Up to 20 percent of cases of LCA are brought on by mutations in the GUCY2D gene, which produces a crucial protein required for the "phototransduction cascade," which transforms light into neural signals in retinal photoreceptor cells.

In two patients, a 19-year-old man and a 32-year-old woman, who had particularly severe rod-based visual deficits, the researchers used higher doses of the gene therapy.

The patients had some, though severely diminished, visual function during the day, at night they were essentially blind, having light sensitivity 10,000–100,000 times lower than normal.

In order to compare the treated eye to the untreated eye and determine the treatment's effectiveness, the researchers only gave the therapy to one eye in each patient.

Allen C. Ho, MD, a professor of ophthalmology at Thomas Jefferson University and Wills Eye Hospital, carried out the retinal surgery. Tests showed that both patients' treated eyes increased their sensitivity to light by thousands of times in low light, significantly reversing the initial visual abnormalities.

In summary, nine complementary techniques were used by the researchers to evaluate the patient's functional vision and light sensitivity. These included tests of involuntary pupil responses to light and room navigation skills in low light.

“Just as striking was the rapidity of the improvement following therapy. Within eight days, both patients were already showing measurable efficacy,” said Artur V. Cideciyan.

Abstract:

Signaling of vision to the brain starts with the retinal phototransduction cascade which converts visible light from the environment into chemical changes. Vision impairment results when mutations inactivate proteins of the phototransduction cascade. Severe monogenically-inherited blindness, Leber congenital amaurosis (LCA), is caused by mutations in the GUCY2D gene, leading to a molecular defect in the production of cyclic GMP, the second messenger of phototransduction. We studied two patients with GUCY2D-LCA who were undergoing gene augmentation therapy. Both patients had large deficits in rod photoreceptor-based night vision before intervention. Within days of therapy, rod vision in both patients changed dramatically; improvements in visual function and functional vision in these hyper-responding patients reached more than 3 log10 units (1000-fold), nearing healthy rod vision. Quick activation of the complex molecular pathways from retinal photoreceptor to visual cortex and behavior is thuspossible in patients even after being disabled and dormant for decades.