Choroideremia is a rare blinding disease resulting from progressive retinal degeneration due to loss-of-function mutations in the gene CHM. Previously, little had been known about the cellular mechanisms underlying choroideremia owing to the limited resolution of current clinically available imaging techniques.
Now, NEI researchers have used advanced multimodal imaging to investigate cellular changes in the living human eye. They found that all subjects with pathogenic mutations in the CHM gene had subclinical structural changes in the retina and widespread enlarged retinal pigment epithelial (RPE) cells.1
“Using adaptive optics [AO], we were able to show that RPE cells were dramatically enlarged in choroideremia,” said Johnny Tam, PhD, at the NEI. “Our study supports the notion that we should start thinking about choroideremia as an RPE-driven disease. When developing treatments for this disease, we should monitor the RPE layer before and after treatment, as this seems to be the most affected layer.”
DISRUPTION. NEI scientists visualized the RPE cell mosaic in the living human eye. Here, fluorescence imaging shows how cells are disrupted in choroideremia.
Multimodal imaging approach. AO allows researchers to “image in vivo at the cellular level, providing a higher clarity and resolution than current clinical imaging technologies,” Dr. Tam said. Although it is not a new technology, “it has not made its way into routine clinical care because it is a complex technology to deploy.”
In their multimodal approach, the NEI team used AO in concert with OCT and with indocyanine green (ICG) to assess the photoreceptor, RPE, and choriocapillaris layers at the cellular level.
The researchers also introduced a strategy for detecting enlarged RPE cells using conventional ophthalmic imaging instrumentation without AO. In this part of their study, late-phase ICG using routine scanning laser ophthalmoscopy revealed retinal structural changes similar to those seen with multimodal imaging, Dr. Tan said.
A structural surprise. In choroideremia, CHM mutations show an X-linked inheritance pattern. However, in this study, subclinical, widespread enlarged RPE cells were present not only in affected males but also in female carriers who carry only one chromosome with an altered CHM gene and do not show clinically significant vision impairment. This finding “was very surprising and unexpected,” Dr. Tam noted.
With regard to the RPE cells, disruptions to the RPE layer in the fovea were greater than those in the photoreceptor or choriocapillaris layers. The research team was also able to show that some photoreceptors were fluorescently labeled, even though they were “structurally and functionally normal.” This finding suggests that the integrity of the RPE blood barrier may be disrupted in choroideremia, which “allows some of the dye to get through and label the photoreceptors,” Dr. Tam said.
Unanswered questions. What happens to enlarged RPE cells? “We would like to longitudinally follow enlarged RPE cells to see what happens to them throughout the natural course of the disease as well as during treatment,” Dr. Tam said.
Bigger picture. “Until now, widespread changes in RPE cells were not easily detected using clinical imaging tools,” Dr. Tam said. “Finding that RPE cells can be so dramatically affected changes the way we view choroideremia and other diseases that impact the RPE layer.”
—Christos Evangelou, PhD
1 Aguilera N et al. Commun Biol. 2022;5(1):893.
Relevant financial disclosures: Dr. Tam—None.
For full disclosures and the disclosure key, see below.
Full Financial Disclosures
Dr. Demirci Aura Bioscience: C; Castle Bioscience: C.
Dr. Moghimi NEI/NIH: S.
Dr. Roth NIH: S.
Dr. Tam None.
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