Gene Therapy Partly Restores Cone Receptors in Eyes of Color Blind Children

Gene therapy has partially restored the function of the retina's cone receptors in two infants who were born entirely color blind, according to a recent study headed by University College London (UCL) researchers.

The research, which was published in the journal Brain, raises hope that the therapy is successfully reactivating the brain's and retina's long-dormant communication connections by utilizing the plastic nature of teenage brain development.

The academically-led study, which uses a novel method to determine whether the treatment is altering the neurological circuits particular to the cones, has been ongoing concurrently with a phase 1/2 clinical trial in children with achromatopsia.

What is achromatopsia?

Achromatopsia is caused by disease-causing variants to one of a few genes. Cone cells, one of the two types of photoreceptors in the eyes along with rods, are affected.

People with achromatopsia are completely color blind because cones are what determine color, and they also have very poor vision in general and dislike bright light (photophobia). Researchers have been attempting to revive the dormant cone cells because although many of them are still present, their cone cells do not send signals to the brain.

Lead author Dr. Tessa Dekker, UCL Institute of Ophthalmology, said, "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."

The research method

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

The two studies test gene treatments that specifically target known achromatopsia-related genes (the two trials are each targeting a different gene). Their main goal is to test the safety of the treatment, while simultaneously checking for vision improvement. The total effectiveness of the treatments has not yet been assessed as all of their results have not yet been compiled.

In the related academic study, the researchers separated emerging post-treatment cone signals from pre-existing rod-driven signals in patients using a novel functional magnetic resonance imaging (fMRI, a type of brain scan), allowing them to directly link any changes in visual function following treatment to the targeted cone photoreceptor system.

They employed a "silent substitution" technique using pairs of lights to selectively stimulate cones or rods. The researchers also had to adapt their methods to accommodate nystagmus (involuntary eye oscillations, or "dancing eyes"'), another symptom of achromatopsia. The outcomes were compared with tests conducted on nine untreated patients and 28 healthy-sighted volunteers.

What did the results say?

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.

Six to fourteen months following treatment, there was convincing evidence for cone-mediated signals originating from the treated eye in the visual cortex of the brain for two of the four children. Before the treatment, the patients showed no evidence of cone function on any tests. After therapy, their measurements closely matched those of trial participants who had normal vision.

A psychophysical test of cone function, which measures the eyes' capacity to differentiate between various contrast levels, was also performed by research participants. This showed there was a difference in cone-supported vision in the treated eyes in the same two children.

According to the researchers, they are unable to establish if the treatment was ineffective in the other two study subjects, whether there were treatment effects that their tests may not have detected, or whether effects are delayed.

Comments from the researchers and study participants

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."