Kanae Fukutsu, MD, PhD
Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Japan
Dr. Keiko Kataoka, professor Hideki Koizumi, and Dr. Adrienne Scott moderated the session on the morning of the third day of Fuji Retina 2024.
Professor Yoko Ozawa from Fujita Medical Innovation Center Tokyo & Eye Center, Fujita Health University, Haneda Clinic, Japan, first talked about the imbalance of choroidal vasculature in eyes diagnosed with age-related macular degeneration (AMD). She examined the choriocapillaris using OCT angiography (OCTA) and showed that among 38 eyes, 18 eyes (47%) had asymmetrical choroidal vasculature. Also, the choriocapillaris flow area (CCFA) ratio was smaller, and the coefficient of variation (CV) of the CCFA ratio, which represents the heterogeneity of the ratio, was more significant in the eyes with asymmetric vasculature. Notably, RPE volume measured by three dimension OCT that indicated RPE atrophy was observed at the site of severe choriocapillaris flow deficit in eyes with imbalanced vasculature. She suggested that the choroidal flow imbalance due to the asymmetric vasculature could contribute to the pathogenesis of AMD.
Next, Dr. Yasuo Yanagi from Yokohama City University, Japan, presented on the characteristics of geographic atrophy (GA) in Asia. The prevalence of GA and the ratio of GA to wet AMD in Asia were significantly lower than in Caucasians. Regarding sex, males were more likely to have GA than females. Furthermore, within Asia, south Asians and east Asians showed a different prevalence of GA, especially the Japanese population, which showed an extremely small prevalence.
Additionally, Dr. Yanagi discussed the prevalence of drusen subtypes among ethnicities. Singaporeans showed a significantly higher prevalence of distinct soft drusen compared to Australians. The Rumoi study conducted in the city of Hokkaido, the northern island of Japan, compared the prevalence of drusen subtypes, and the prevalence of pachydrusen was much higher compared to soft drusen or reticular pseudodrusen. This result indicated that the prevalence of pachydrusen might be higher than previously thought. However, pachydrusen was not associated with the incidence of GA, possibly because pachydrusen decrease or disappear over time while soft drusen increase over time. From these results, Dr. Yanagi discussed the potential reason for the low prevalence of GA in East Asian populations, especially in Japan. He suggested that choroid thickness, ethnicity, environmental and lifestyle factors could be affecting the low prevalence of GA.
The third speaker was Professor Tarek S. Hassan from Oakland University, William Beaumont School of Medicine in the USA. His talk focused on the next-generation of treatments for GA. GA is caused by both macrophage overactivation and complement dysregulation. Its pathological mechanism is related to macrophage repolarization. The macrophages polarized as M1 tend to accelerate dry AMD, the ones polarized as M2 cause wet AMD, and resolution macrophages have an anti-inflammatory effect. Controlling macrophage polarization could be the key to rescuing the weakening (but not dead) RPE and photoreceptor cells that cause GA.
Polarization control of macrophage can be achieved by manipulating the activity of receptors called SIGLECS (Sialic acid-binding immunoglobulin-like lectins). SIGLECS are expressed on all immune cells, and sialic acid is found in every vertebrate cell. Sialic acid serves as an immune marker recognized by SIGLECS on immune cells. SIGLECS on macrophages bind to sialic acid and control the immune system, repolarizing macrophages to a resolution phenotype.
AVD-104 is a novel sialic acid-coated nanoparticle that repolarizes overactivated macrophages and inhibits the overamplified complement system in AMD. In vitro studies demonstrated that AVD-104 reduced inflammatory cytokines, including TNF-α, IL-6, and IL-12. In vivo, AVD-104 rescued light-induced retinal degeneration in mice and inhibited macrophage infiltration and MAC deposition in a dose-dependent manner in the laser-induced CNV mouse model.
Then, Prof. Hassan showed the results of a Phase 1 clinical trial. AVD-104 was given as a single dose to 30 participants with subfoveal lesions and poor vision to assess the safety of the drug. The trial demonstrated that AVD-104 was safe, with only one case of mild inflammation. AVD-104 also improved vision in some patients. GA lesion growth analysis showed that it slowed atrophy progression compared to the fellow eye. Now, the US SIGLEC study is actively enrolling and comparing AVD-104 to another comparator drug.
Next, Professor Hideki Koizumi from the University of the Ryukyus, Japan, discussed the relationship between scleral thickness and pachychoroid diseases. Previously, Prof. Koizumi’s group reported that the scleral thickness measured by anterior segment OCT was greater in central serous chorioretinopathy (CSC) patients than in the controls. However, the mechanism of how scleral thickness affects the clinical manifestation of pachychoroid remains unknown.
Professor Koizumi utilized the multimodal imaging-based classification system for CSC recently introduced by the CSC International Group, which categorizes CSC cases into “simple CSC” or “complex CSC”. The presented study aimed to evaluate the association between scleral thickness and this new classification of CSC.
Two hundred seventeen eyes with CSC underwent multimodal imaging examinations. Sclera thickness was measured under the rectus muscles in four directions using anterior segment OCT. 167 eyes were classified into simple CSC and 50 into complex CSC. In univariate analysis, the complex CSC group showed a significantly higher age, higher male ratio, a higher ratio of bilateral involvement, lower BCVA, greater subfoveal choroidal thickness, and, importantly, thicker sclera in all four directions.
Prof. Koizumi discussed that CSC and uveal effusion syndrome could be on the same “pachy-sclera” disease spectrum, and complex CSC could be positioned between simple CSC and uveal effusion syndrome. He speculated that the thicker sclera in complex CSC stems from congenital differences and concluded that scleral thickness may determine the clinical manifestations of CSC.
Dr. Keiko Kataoka from Kyorin University School of Medicine, Japan, then presented on the prediction of complete SRF resolution on first presentation of acute CSC. She retrospectively reviewed acute CSC cases, excluding bilateral or recurrent cases. 48 eyes in 48 patients were analyzed to evaluate predictors of persistent SRF in first-time presenting CSC. They were divided into the SRF-resolved and SRF-persistent groups, depending on the presence of SRF at six months from the onset of symptoms. She hypothesized that RPE function is the critical factor in the persistence of SRF and focused on autofluorescence images (FAF). FAF alteration was defined as a mixed autofluorescence, and among the cases, the persistent group showed a significantly higher percentage of FAF alterations larger than one disc diameter both in the affected and the fellow eyes.
The persistent group was significantly older and had a worse baseline BCVA than the resolved group. Dr. Kataoka also performed multiple logistic regression analysis to identify the independent variables that predicted the presence of SRF six months from the onset.
As a result, age, central retinal thickness, and FAF alterations in the fellow eye (not the affected eye) were found to predict persistent SRF in acute CSC. She then discussed the need to elucidate the underlying mechanism of this result, mentioning the possibility of congenital structural differences or genetic background.
