Gene therapy for achromatopsia in children partly restores cone function

Gene therapy for achromatopsia in children partly restores cone function
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A new study by University College London has found gene therapy for achromatopsia in children partly restored cone function.

Achromatopsia is a rare inherited condition that causes sensitivity to bright light and loss of colour vision. It affects around one in 30,000 to 40,000 people, and common symptoms include partial or total colour blindness, reduced visual acuity, sensitivity to bright light and shaking eyes.

The findings, published in Brain, pave the way for treatment that effectively activate previously dormant communication pathways between the retina and the brain, drawing on the plastic nature of the developing adolescent brain.

Achromatopsia in children

The study is running alongside a phase 1/2 clinical trial in children with achromatopsia, using a new way to test whether the treatment is changing the neural pathways specific to the cones.

Achromatopsia is caused by disease-causing variants of one of a few genes. It affects cone cells which are one of two types of photoreceptors in the eyes. People with achromatopsia are completely colour blind, have poor vision, and find bright light uncomfortable. As a result, cone cells do not send signals to the brain, but many remain present, so researchers have been seeking to activate the dormant cells.

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.”

Gene therapy that treats colour blindness

The study involved four young people with achromatopsia aged 10 to 15 years old, who were involved in two trials led by Professor James Bainbridge at UCL and Moorfields Eye Hospital.

The two trials are testing gene therapies targeting specific genes known to be related to achromatopsia. The primary aim is to understand if the treatment is safe and whether it improved vision. Their results have yet to be fully compiled, so the overall effectiveness of the treatments is not yet proven.

One of the studies employed a novel functional magnetic resonance imaging (f MRI) mapping approach to separate emerging post-treatment cone signals from existing rod-driven signals in patients. This allowed the researchers to note any changes in visual function after treatment. They then employed a technique using pairs of lights to selectively stimulate cones or rods. The researchers adapted their methods to accommodate involuntary eye oscillations. The results were compared to data from nine untreated patients and 28 volunteers with normal vision.

The four children were treated with gene therapy in one eye to compare the effectiveness with the untreated eye. In two of the children, the researchers found strong evidence for cone-mediated signals in the brain’s visual cortex coming from the treated eye six to 14 months after treatment. This is a significant development as, before treatment, the patients showed no evidence of cone function. Following the treatment, the two children’s measures resembled those of normally sighted study participants.

The study participants also took part in a psychological test of cone function, which assesses the ability of the eyes to distinguish between different contrasts. This highlighted a difference in cone-supported vision in the treated eyes in the same two children.

The researchers also noted that they cannot confirm whether the treatment for achromatopsia was ineffective in the other two study participants, if there may have been treatment effects that were not picked up in the tests, or if the effects were delayed.

Co-lead author Dr Michel Michaelides (UCL Institute of Ophthalmology and Moorfields Eye Hospital), 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 signalling pathways that have been dormant for years.

“We are still analysing 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.”


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