ARVO 2025: Lipid metabolism altered by CFH (Y402H) polymorphism and chronic oxidative stress in iPSC-derived RPE cells

At ARVO 2025, in Salt Lake City, Utah, Peng Shang, PhD, talked about her presentation on how the Y402H polymorphism of Complement Factor H (CFH), a major genetic risk factor for AMD, and chronic oxidative stress affect the lipid profile of retinal pigment epithelial (RPE) cells.

Video Transcript:

Editor's note: The below transcript has been lightly edited for clarity.

Peng Shang, PhD:

Hi. My name is Peng Shang, and I'm from Doheny Eye Institute. I'm actually a Doheny scientist. I work in the parent lab, and I work on age-related macular degeneration. So my presentation at ARVO this year is actually on how the cigarette smoke extract, and then the CFH polymorphism influence the lipid metabolism in the RPE, and then to evaluate how they are involved in the AMD pathogenesis.

You know, I work on AMD, and AMD is a prevalent disease among the elderly, and it actually affects hundreds of millions of people globally, and still remains the main cause of vision loss and with very limited treatment options for most of the patients, and it is actually a multi-factorial disease. Although aging is a primary factor for this disease, it is also driven by genetic and environmental factors. So one of the most prominent gene variants associated with the disease is called complement factor age. So it actually increased the risk of AMD, developing AMD, by 3 to 6 times. Depends on, you know, if it's a homozygous or heterozygous, and smoking is one of the most significant environmental factors. It can accelerate the disease onset by, I think it's, remember, it's 4 to 6 years. So it's a lot, and when it combines with the genetic variant, the complement factor, HSNP, it can increase the risk of developing late AMD, up to 34 votes. So we know that lipids, I also work on lipids, so lipids play very important roles in energy production, membrane structures, and intracellular signaling.

So there are a lot of studies have already shown that the regular lipid metabolism is significantly involved in AMD pathogenesis. But the molecular mechanism through which how the genetic and environmental factors regulate the lipid metabolism, AMD, in the RPE and AMD is not very clear. So that led us to investigate how smoking, and then the CFH genotype, the polymorphism, influence the lipid homeostatis in the RPE, and then, therefore in the AMD pathogenesis. RPE plays an essential role in maintaining the retina health, homeostasis, so actually the dysfunctional dysregulation of RPE function is associated with lot of eye diseases, especially the retina diseases. I am interested in AMD because we have lot of resources. We have human samples from the AMD patients, and we also have a lot of IPS derived RPE lines. So that's why we focus on this specific field. Very limited treatment options for the patients, right? Mainly these is targeted to the wet AMD. There are a lot of anti-VEGF therapies developed for that. But, you know, I think 85% of the AMD patients, they have the dry AMD, and there is, so far, there is no effective treatments for that. I guess why it's so difficult to get an effective therapy for that is because AMD is a multi-factorial disease.

There are a lot of studies have shown, these biological process or pathways were altered in the AMD samples or tissue, nut there are also other pathways or processes involved in the same process, so it's actually very, very complicated, very complex pathology. I think advantage of our research is that we have a lot of samples from the human patients. We have actually hundreds of, probably thousands of, actually thousands of human samples from the patients, graded, you know, different AMD levels. Then, we also have the IPS RPE cells from the donors, and we recently, we have done a lot of omics experiment that we can, you know, have an overview of the all those molecular biological molecule profiles in these samples. We utilize those bio-informatic tools to analyze what pathways processes [are] actually altered in those AMD samples. In our case, we are interested in CFH polymorphism. So you know, our samples categorize into CFH low-risk and CFH high-risk groups. So we compare what is the difference in the protein profile or lipids profile or metabolized profile?

So we have these big datasets, now we are kind of like digging into these big dataset, and then to see what clues that we can get from these data. Fortunately, we got very interesting and promising, I think, data from our lipid domics, actually lipid metabolism these days is as very, very hot topic in the AMD pathology. I think in the past maybe decades, why the lipid metabolism was not that well investigated, because maybe was because of the limitation of the technology that can accurately quantify those lipid metabolites in the samples.