Gene Therapy Successfully Restores Cone Function in Colorblind Children

The study, which took advantage of the plasticity of the emerging neural networks in the developing teenage brain, provides optimism that the therapy is successfully reactivating brain-retinal communication channels that had remained dormant.

Academic research has been conducted to determine whether the medicine is changing the brain circuits specific to the cones in conjunction with a phase 1/2 clinical study in children with achromatopsia.

Achromatopsia is caused by one or a few genes having disease-causing mutations. It has an impact on cone cells, one of the two types of photoreceptors in the eyes (the other being rods). Because cones are crucial for color vision, people with achromatopsia are completely colorblind in addition to having very poor overall vision and finding bright light painful (photophobia). Since the dormant cone cells exist but do not send messages to the brain, researchers are working to revive them.

"Our study is the first to directly confirm popular belief that gene therapy given to kids and teenagers can successfully activate dormant cone photoreceptor pathways and evoke visual signals these patients have never before experienced. We are demonstrating the possibility of using the brain's plasticity, which may be especially capable of adjusting to tremor," said Dr. Tessa Dekker, the study's lead author.                                                                                                               

Four achromatopsiac teenagers, aged 10 to 15, were enrolled in the study. They took part in two trials at Moorfields Eye Hospital and UCL that were overseen by Professor James Bainbridge and funded by MeiraGTx-Janssen Pharmaceuticals.

The two studies focus on gene therapies that specifically target known achromatopsia-related genes (each trial is targeting a different gene), and their main objective is to assess the safety of the treatment while assessing whether eyesight has improved or not. The overall effectiveness of the treatments is unknown as a result of their incomplete information gathering.

The researchers used a novel functional magnetic resonance imaging (fMRI, a type of brain scan) mapping technique to distinguish newly appearing post-treatment cone signals from pre-existing rod-driven signals in patients. This allowed them to link any changes in visual function following treatment directly to the targeted cone photoreceptor system. Pairs of lights were used in a "silent substitution" technique to target cones or rods for stimulation.

Each of the four children received gene therapy for one eye, which allowed doctors to gauge the treatment's effectiveness in comparison to the unaffected eye.

Two of the four children failed all tests used to diagnose cone function prior to therapy, but after therapy their measurements were quite similar to those of the research participants who were normally sighted, and there was convincing evidence for cone-mediated signals originating from the treated eye in the visual cortex of the brain six to fourteen months after treatment.

Participants also completed a psychophysical test of cone function, which examines the eyes' ability to distinguish between different contrast levels, and this showed that the identical two kids' treated eyes have different cone-supported vision.

The researchers claim that they are unable to determine if the treatment failed in the other two study participants, whether there were treatment effects that their tests might not have picked up, or whether effects are delayed.                                   

The UCL Institute of Ophthalmology and Moorfields Eye Hospital's Dr. Michel Michaelides, co-lead author and co-investigator on both clinical trials, said: "In our trials, we are examining whether delivering gene therapy early in life may be most effective while the neural circuits are still developing. According to our research, the brain is remarkably flexible, raising the possibility that medicines could reawaken signaling networks that had been dormant in order to facilitate visual activities.

With successful outcomes and additional clinical trials, we anticipate significantly improving the vision of those suffering from inherited retinal diseases. We are still analyzing the results from our two clinical studies to determine whether this gene therapy can significantly improve the day-to-day eyesight of achromatopsia patients.

By providing unmatched sensitivity to treatment effects on neural processing and new and in-depth insight into when and why these therapies are most effective, the use of these new tests in upcoming clinical trials, according to Dr. Dekker, "could speed up the testing of ocular gene therapies for a variety of conditions."

One of the study participants commented, "Watching changes to my vision has been extremely exciting, so I'm curious to see whether there are any additional changes and where this treatment as a whole might lead in the future."

Given that I've become accustomed to having low vision, dealt with issues related to it throughout my life, and have made accommodations for it, it is actually challenging for me to comprehend what or how many effects a major improvement in my eyesight might have.

The Ardalan Family Scholarship, the Persia Educational Foundation Maryam Mirzakhani Scholarship, the Sir Richard Staines Scholarship, the Economic & Social Research Council, MeiraGTx, Retina UK, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, Foundation Fighting Blindness, Wellcome, and the Sir Richard Staines Scholarship at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology supported the study.

By UNIVERSITY COLLEGE LONDON