Study: Researchers find new mechanisms that cause blindness, opening the door to future treatments

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There are many mysteries surrounding the mechanism of action of the CERKL gene, which causes retinitis pigmentosa and other hereditary vision diseases. Researchers from the University of Barcelona have outlined how the lack of the CERKL gene alters the ability of retinal cells to fight oxidative stress generated by light and drives cell death mechanisms that lead to blindness.

The study,¹ published in Redox Biology, adds to the discussion of characterizing hereditary blindness and identifying key mechanisms to address future treatments based on precision medicine.

Gemma Marfany, PhD, a member the University of Barcelona’s biology faculty, led the study. She also is a part of the Rare Diseases Networking Biomedical Research (CIBERER).

According to a University of Barcelona news release, the research study, carried out with animal models, is the result of close collaboration with teams from the Sant Joan de Déu Research Institute (IRSJD), the University of Valencia, the Severo Ochoa Molecular Biology Center (CSIC -UAM) and the Hospital 12 de Octubre Research Institute in Madrid.

The researchers found for the first time that when the CERKL gene is missing, retinal cells are permanently stressed.

“This basal exacerbated state means that when additional oxidative damage is caused — as with continuous light stimulation — the cells are no longer able to respond because they can no longer activate antioxidant response mechanisms,” Marfany noted in the news release.

Marfany pointed out in the release the retina is permanently inflamed.

“As a consequence, retinal cells activate cell death mechanisms, such as necroptosis and ferroptosis,” she said in the news release. “Although the experiments have been performed in mice, these alterations allow us to explain how and why photoreceptor cells die in patients and cause blindness," she adds.

The retina’s response to light when the CERKL gene is missing

Researchers noted the retina is a neural tissue that is constantly subjected to light stress — and therefore oxidative stress — and retinal cells must activate antioxidant mechanisms to cope with it. The new study is based on a transgenic mouse model in which the CERKL gene has been eliminated using gene editing techniques (CRISPR).¹

According to the university’s news release, the researchers noted in the study that when they applied electrophysiological techniques, it was shown that the retina of these mice without CERKL progressively degenerated in a manner similar to that of human patients. But how is the physiological activity of altered photoreceptors when CERKL is mutated?

Marfany pointed out that amid the multidisciplinary collaboration between teams, the researchers have been able to combine different approaches to delve into the pathology caused by mutations in CERKL.

“Transcriptomics techniques have revealed how the retina responds to light stress when it lacks the CERKL protein,” she said in the news release. “Metabolomic analysis has identified the altered cellular biochemical pathways that do not allow the retina to cope with the oxidative damage generated by excess light and end up causing the death of photoreceptors.”

Moreover, Marfany noted in the release that researchers maintain that CERKL is a resilience gene in oxidative stress.

“All this knowledge complements genetic studies and opens up new avenues for future therapeutic approaches,” she explained in the news release.

The function of genes in the design of therapies

One in 3000 people in the world has some form of hereditary retinal dystrophy, one of the rare diseases with the highest incidence in the population. So far, a total of 90 genes associated with retinitis pigmentosa have been identified, but there are more than 300 genes that can affect vision.¹

Marfany pointed out it is key to make a solid genetic diagnosis of patients and identify the gene that causes the disease.

“We now know that about 3% of patients with retinitis pigmentosa in Spain have mutations in the CERKL gene,” Marfany said in the news release. "A good part of the efforts in rare vision diseases is focused precisely on this genetic diagnosis of patients, but to understand the physiological effect of these mutations it is necessary to analyze what happens in the cells of the retina.”

Moreover, the researchers noted in the University of Barcelona news release that identifying the gene that causes the disease and its physiological function are foundational for designing a precision or personalized therapy. In the case of gene therapy, it is usually expensive — in time and money — and only accessible to a limited number of patients.¹

“Now, if we know better which pathways are altered when the CERKL gene is absent, we can think about how to compensate for these pathways: for example, with drugs that can act on these metabolic pathways and restore the correct functioning of retinal neurons and return to a more homeostatic state,” Marfany said in the university news release. “This type of therapeutic approach is much more affordable, and if it slows down the progression of the disease, it could benefit many patients.”

According to the news release, the university’s Research Group on Human Molecular Genetics has an outstanding track record of more than 25 years in the study of the genetic basis of vision diseases. The researchers led the way in identifying an unknown gene — CERKL — as the cause of retinitis pigmentosa (The American Journal of Human Genetics, 2004) in a study of a family with several affected children.¹

Going forward, Marfany said the researchers will work to understand how mutations in the CERKL gene cause photoreceptor death in patients.

“In the future, we want to generate new models of the disease with human retinal organoids, and design precision therapy strategies — gene therapy and also with drugs — based on molecules that allow us to reverse the most severe symptoms of the disease,” Marfany concluded in the news release.

Reference:

1. Rocío García-Arroyo, Elena B. Domènech, Carlos Herrera-Úbeda, Miguel A. Asensi, Cristina Núñez de Arenas, José M. Cuezva, Jordi Garcia-Fernàndez, Federico V. Pallardó, Serena Mirra, Gemma Marfany, Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress, Redox Biology, Volume 66, October 2023, 102862, ISSN 2213-2317, DOI: 10.1016/j.redox.2023.102862.