Precision Medicine Therapy Improves Congenital Blindness

In an initial clinical trial, researchers found that a new precision medicine therapy for a common form of congenital blindness was safe and improved patients’ vision, according to a study published in iScience.

Researchers from the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania developed a gene therapy that delivers working copies of GUCY2D to the eyes of patients who have severe vision impairments caused by mutations in the gene.

Each of the first three patients treated experienced improvements in some aspect of vision without serious side effects.

“We found sustained improvements in both day and night vision, even with a relatively low dose of the gene therapy,” said study lead author Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology in the Perelman School of Medicine.

The GUCY2D gene is one of about 25 different human genes with mutations that can cause problems in the retina, resulting in severe vision impairment from birth or early childhood. This family of inherited retinal disorders is collectively known as Leber congenital amaurosis (LCA), and accounts for a large portion of blindness in children worldwide.

Normal copies of GUCY2D encode an enzyme in the key pathway that light-sensitive rod and cone cells in the retina use to convert light into electrochemical signals. A lack of this enzyme blocks the recovery of this pathway, preventing the reset needed for further signaling. As a result, the signal from rod and cone cell becomes very weak, which equates to severe vision loss.

Even for adults who have lived with this condition for decades, it’s often the case that many light-sensing retinal cells remain alive and intact despite their dysfunction. So, adding functional copies of GUCY2D through gene therapy could get those cells working again, restoring some vision.

In 2019, researchers from Penn Medicine began the first clinical trial of a GUCY2D gene therapy. The treatment consists of a solution of a harmless virus that carries the gene and is injected beneath the retina, initially in just one eye per patient.

The team is following each patient for two years after treatment. In the new study, researchers described their findings after nine months in the first three patients treated.

The first patient experienced a substantial increase in light-sensitivity in rod cells, which are more light-sensitive than cone cells and are primarily responsible for low-light or night vision. This patient also showed improved pupil responses to light.

The second patient showed a smaller but sustained increase in light-sensitivity in rod cells, beginning about two months after the gene therapy.

While the third patient showed no improvement in rod cell sensitivity, they did show significantly improved visual acuity over the nine-month follow-up period. Researchers tied this improvement to better function in the patient’s cone cells, the predominant cells for daylight and color vision.

Patients didn’t experience any serious adverse side effects, and any side effects that occurred in the patients’ retinas resolved.

The team noted that the gene therapy dose used in these first three patients was the lowest of the doses researchers plan to use in the study. The group expects to see continued safety and greater efficacy in patients who enroll later and will receive higher doses.

“These initial results from the first-ever trial of a GUCY2D gene therapy are very encouraging and will inform our ongoing and future trials of this therapy,” said Artur V Cideciyan, PhD, a research professor of Ophthalmology in the Perelman School of Medicine.

Researchers have previously leveraged precision medicine approaches to treat blindness. In December 2020, a team from The Ohio State University Wexner Medical Center created a precision medicine method to determine patients’ genetic risk of developing glaucoma, with the goal of reducing glaucoma-related blindness in the future.

“The application of genetic risk models is being applied with the goal to improve outcomes for a variety of conditions, such as obesity, heart disease, type 2 diabetes and breast cancer. We hypothesize that a combination of genes that have already been linked to eye pressure will also predict individuals who will have pressure spikes versus those who have a more flat pressure profile,” said Sayoko Moroi, MD, PhD, an ophthalmologist and chair of the Department of Ophthalmology and Visual Sciences at the Ohio State Wexner Medical Center.

“In our research, we’re moving beyond clinical risk factors of glaucoma, such as eye pressure, older age and a thin cornea, to include these genetic models that may improve our ability to diagnose patients earlier and to know which patients have a risk for large pressure fluctuations and who we need to treat more aggressively to flatten their eye pressure profile.”