A study recently published in JCI Insight evaluated the connection of light exposure and retinal dystrophies in the first study to incorporate human subjects.
Give me some background first.
Progressive photoreceptor cell death leads to inherited retinal dystrophies (IRDs)—known to be a major cause of irreversible vision loss. Some of these include:
- Retinitis pigmentosa (RP)
- Achromatopsia
- Macular dystrophy
Treatment for this can be difficult, as IRDs can be caused by mutations in more than 250 different genes.
Go on…
The eyes shut homolog (EYS) gene is “predominantly expressed in the retina and especially in photoreceptor cells,” and has been reported as one of the most frequent causes of RP.
However: EYS is typically missing or interrupted in many of the most common investigational animal models, leading to difficulty in evaluating EYS-associated retinal dystrophies (EYS-RDs).
Even further: Along the lines of these animal models, zebrafish studies have shown that EYS is expected to be involved in the maintenance of the morphological structure of photoreceptors and regulating protein transport to the outer segments of photoreceptor cells.
And how does this lead to the study?
First: Investigators noted that human induced pluripotent stem cells (iPSCs) can generate human organ-specific cells in order to test human samples.
Thus: For this study, researchers utilized iPSCs to generate retinal organoids and investigate EYS-RDs—including EYS function and pathogenesis.
Why: The researchers maintained that human samples were imperative to investigate to gain a better understanding of EYS and the pathogenesis of IRDs.
Who was included in the study?
iPSCs were generated from two patients with EYS-RD who both patients had homozygous variants in the EYS gene; Two healthy iPSCs from a previous study on amyotrophic lateral sclerosis (ALS) gene analysis were used for control.
Note: Patient 1 had a degenerated macular region and almost no central vision. While patient 2 had subtle cone function in electroretinography (ERG) and spared central and temporal visual fields.
Findings?
Retinal organoids were generated from each iPSC and observed and analyzed. Following analysis, it was suggested that the EYS protein doesn’t affect retinal development.
However: less EYS or EYS-positive punctate structures were noted in the cilia or outer segment (OS) regions of photoreceptor cells in EYS-RD retinal organoids.
What else should I know?
Researchers hypothesized that G protein-coupled receptor kinase 7 (GRK7) was also associated with EYS and tested this theory via immunostaining.
- Quick refresh: GRK7 is a protein involved in the shutoff and recovery of the photoresponse.
The findings: In the RD organoids, “GRK7 dysfunction caused by mutant EYS led to the over response to light stimuli and resulted in cell death via ROS generation,” the study authors noted
Go on…
It was also observed that light-induced cell death in the RD organoids was especially caused by short-wavelength light.
Plus: Light stimulation triggered photoreceptor cell death in EYS-RD retinal organoids and further showed that blue light is especially lethal.
Limitations?
Per the authors: Limitations included the fact that a limited number of iPSCs were utilized in this study. In addition, they spoke to how variation in the iPSC clones could affect certain results.
Take home.
Ultimately, although further research is necessary to address unknowns, this was the first study to investigate this association with human samples.
The study authors concluded: “Our data demonstrate that photoresponse integrity is impaired by EYS mislocalization, and it would be a potential therapeutic approach for patients with EYS-RD to restrict the exposure to high-energy short-wavelength light.”