Gene Therapy Successfully Restores Cone Function in Colorblind Children

Eye DNA Genetics Concept

Could gene therapy cure colorblindness in the future?

Following treatment, two of the four children’s measurements of cone function closely resembled those of normal-sighted research participants.

According to a recent study led by University College London researchers, two children who were born completely colorblind have had their retinal cone receptor function partially restored through the use of gene therapy.

The findings, published in Brain, provide hope that the treatment is effectively activating previously dormant communication channels between the retina and the brain, taking advantage of the plastic nature of the developing teenage brain.

The academically-led study, which uses a new method to determine if the treatment is changing the neural pathways specific to the cones, has been running alongside phase 1/2 clinical trial in children with achromatopsia.

Achromatopsia is caused by disease-causing variants to one of a few genes. It affects cone cells, which are one of two kinds of photoreceptors in the eyes (the other being rods). Because cones are responsible for color vision, people with achromatopsia are completely colorblind, as well as possess very poor overall vision and find bright light uncomfortable (photophobia). Their cone cells do not transmit signals to the brain, but plenty of them remain, so researchers have been looking for ways to activate the dormant cells.

Lead author Dr. Tessa Dekker (UCL Institute of Ophthalmology) states, “Our study is the first to directly confirm widespread speculation that gene therapy offered to children and adolescents can successfully activate the dormant cone photoreceptor pathways and evoke visual signals never previously experienced by these patients. We are demonstrating the potential of leveraging the plasticity of our brains, which may be particularly able to adapt to treatment effects when people are young.”

Four adolescents with achromatopsia, aged 10 to 15, participated in the study. They took part in two trials led by Professor James Bainbridge at UCL and Moorfields Eye Hospital and funded by MeiraGTx-Janssen Pharmaceuticals.

The two trials investigate gene therapies that target certain genes that are known to be involved in achromatopsia (the two trials are each targeting a different gene). Their primary objective is to assess the treatment’s safety while evaluating whether or not eyesight has improved. Their findings have not yet been completely compiled, thus the overall efficacy of the treatments is unknown.

The researchers employed a novel functional magnetic resonance imaging (fMRI, a kind of brain scan) mapping method to distinguish emerging post-treatment cone signals from existing rod-driven signals in patients, enabling them to identify any changes in visual function after treatment directly to the targeted cone photoreceptor system. They used a ‘silent substitution’ technique to selectively stimulate cones or rods using pairs of lights. The researchers also had to modify their methods to accommodate nystagmus (involuntary eye oscillations, or ‘dancing eyes’), another symptom of achromatopsia. The findings were compared to tests involving nine untreated patients and 28 volunteers with normal eyesight.

Each of the four children was treated with gene therapy in one eye, enabling doctors to compare the treatment’s effectiveness with the untreated eye.

For two of the four children, there was strong evidence for cone-mediated signals in the brain’s visual cortex coming from the treated eye, six to 14 months after treatment. Before the treatment, the patients showed no evidence of cone function on any tests. After treatment, their measures closely resembled those of normal-sighted study participants.

The study participants also completed a psychophysical test of cone function, which assesses the ability of the eyes to distinguish between different levels of contrast. This showed there was a difference in cone-supported vision in the treated eyes in the same two children.

The researchers say they cannot confirm whether the treatment was ineffective in the other two study participants, or if there may have been treatment effects that were not picked up by the tests they used, or if effects are delayed.

Co-lead author Dr. Michel Michaelides (UCL Institute of Ophthalmology and Moorfields Eye Hospital), who is also co-investigator on both clinical trials, said: “In our trials, we are testing whether providing gene therapy early in life may be most effective while the neural circuits are still developing. Our findings demonstrate unprecedented neural plasticity, offering hope that treatments could enable visual functions using signaling pathways that have been dormant for years.

“We are still analyzing the results from our two clinical trials, to see whether this gene therapy can effectively improve everyday vision for people with achromatopsia. We hope that with positive results, and with further clinical trials, we could greatly improve the sight of people with inherited retinal diseases.”

Dr. Dekker added: “We believe that incorporating these new tests into future clinical trials could accelerate the testing of ocular gene therapies for a range of conditions, by offering unparalleled sensitivity to treatment effects on neural processing, while also providing new and detailed insight into when and why these therapies work best.”

One of the study participants commented: “Seeing changes to my vision has been very exciting, so I’m keen to see if there are any more changes and where this treatment as a whole might lead in the future.

“It’s actually quite difficult to imagine what or just how many impacts a big improvement in my vision could have, since I’ve grown up with and become accustomed to low vision, and have adapted and overcome challenges (with a lot of support from those around me) throughout my life.”

Reference: “A demonstration of cone function plasticity after gene therapy in achromatopsia” by Mahtab Farahbakhsh, Elaine J Anderson, Roni O Maimon-Mor, Andy Rider, John A Greenwood, Nashila Hirji, Serena Zaman, Pete R Jones, D Samuel Schwarzkopf, Geraint Rees, Michel Michaelides and Tessa M Dekker, 24 August 2022, Brain.
DOI: 10.1093/brain/awac226

The study was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, the Economic & Social Research Council, MeiraGTx, Retina UK, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, Foundation Fighting Blindness, Wellcome, Ardalan Family Scholarship, the Persia Educational Foundation Maryam Mirzakhani Scholarship, and the Sir Richard Stapley Educational Trust.

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