New Imaging Approach Elucidates Vision Restoration After Gene Therapy in Achromatopsia


Researchers used novel functional MRI approaches to better measure the effects of gene therapy in children in current clinical trials.

Researchers from University College London (UCL) have affirmed the ability of gene therapy to awaken dormant cone-signaling pathways, restoring visual function in achromatopsia (ACHM) and further elucidating neural plasticity in children.1

“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,” lead author Tessa Dekker, PhD, associate professor, UCL Institute of Ophthalmology and UCL Psychology & Language Sciences, said in a statement.2 “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.”

Dekker and colleagues used novel imaging approaches to test for new cone function after gene therapy in 4 children with CNGA3- or CNGB3-associated ACHM aged between 10 and 15 years enrolled in phase 1/2 clinical trials (NCT03758404 and NCT03001310) also being conducted at UCL. The trials are sponsored by MeiraGTx and Janssen and led by James Bainbridge, MBBS, PhD, professor and chair, retinal studies, UCL and Moorfields Eye Hospital. Data from these children were compared against a dataset of untreated patients with ACHM (n = 9) and normal-sighted control participants (n = 28) tested under the same circumstances.

“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,” co-lead Michel Michaelides, BSc, MB BS, MD(Res), FRCOphth, FACS, professor, ophthalmology, UCL Institute of Ophthalmology and Moorfields Eye Hospital, added to the statement.2

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“We are still analyzing the results from our 2 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,” Michaelides added.2

Dekker, Michaelides, and colleagues used a novel functional MRI (fMRI) mapping approach to separate cone signals between pre-existing rod signals and new, post-treatment cone signals, allowing them to pinpoint any changes in visual function related to cone photoreceptors. They achieved this with a ‘silent substitution’ technique that embedded a chromatic pair that induced different levels of activity in cones but identical levels of activity in rods. This approach also allowed them to observe the degree of preservation of neuronal retinotopic tuning profiles in the newly engaged pathways.

In addition to the fMRI measures, the researchers employed complementary psychophysical tests to evaluate cone contrast perception and utilization of new cone signals as well as validate the fMRI approach. Psychophysical tests included 4AFC square localization and a ridge motion discrimination task.

“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,” Dekker added.2

After gene therapy, the fMRI imaging approach revealed that 2 patients had significantly improved levels of contrast sensitivity thresholds in treated eyes, although improvements in best corrected visual acuity (BCVA) were not observed. Researchers were also able to observe a new, cone-mediated retinotopic map in the visual cortices of these 2 patients, expanded cortical visual field coverage, and expanded population receptive field size.

“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,” a study participant commented.2 “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.”

The researchers concluded that even after 10-15 years of life, gene therapy can activate dormant cone photoreceptor pathways in patients with ACHM and elicit visual signals new to these patients. They also concluded that in visual cortex, retinotopic spatial tuning to cone-mediated signals could be achieved after gene therapy. The work demonstrates that the neural infrastructure for cone function is preserved even after a long period of deprivation. Limitations include that more research remains to be done on how to maximize the effects of gene therapy and the study’s method of only treating the worse eye in terms of BCVA may also have affected results.

1. Farahbakhsh M, Anderson EJ, Maimon-Mor RO, et al. A demonstration of cone function plasticity after gene therapy in achromatopsia. Brain. 2022; awac226, doi: 10.1093/brain/awac226
2. Gene therapy for completely colourblind children partly restores cone function. News release. University College London. August 24, 2022.
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