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AMD Research News

Posted by Ilena Di Toro | Posted on May 24, 2022

Age Related Macular Degeneration (AMD) is a vision condition that no one wants. As the name suggests, this affects persons over the age of 50. It comes about when the macula, the part of the retina that controls sharp, straight-ahead vision, becomes damaged over time. While it doesn’t lead to total blindness, losing central vision makes it hard to read, cook, drive and see faces.

As with many health conditions, research is ongoing to learn more about AMD and what, if any drugs, can be used to treat it. There are two research projects that have provided insights into this condition.

Stems Cells and Drug Candidates
Scientists, from the National Eye Institute (NEI), part of the National Institutes of Health (NIH) used a stem cell model of dry AMD to screen for drugs that might be able to slow or halt disease progression. Two drugs were found to prevent the model from developing key characteristics. Namely the accumulation of drusen, which are lipid-rich deposits in the retina, and atrophy of retinal pigment epithelium cells. In AMD, the retinal pigment epithelium cells shrink and die and that leads to loss of vision.

Previous studies showed that some AMD patients have variants in genes responsible for regulating the alternate complement pathway, an important part of the immune system. What researchers didn’t know was how the variants led to the disease. One theory is that patients with the variants didn’t have the ability to regulate the alternate complement pathway. When the alternate complement pathway is activated, anaphylatoxins, a protein that modifies inflammation, among other biological functions, is formed.

To test this theory, scientists exposed 10 induced pluripotent stem cells (iPSC) derived retinal pigment epithelium cell lines involving different genetic variants to anaphylatoxins derived from human serum. They thought this would act as a surrogate for age-induced increase in alternate complement pathway that was observed in the eyes of patients with AMD.

The iPSC derived retinal pigment epithelium cells that were exposed to the human serum developed several characteristics. There was the formation of drusen and atrophy of retinal pigment epithelium cells, which occur during the advanced stages of AMD. The disease progression was worse in iPSC-derived retinal pigment epithelium cell lines from patients with high-risk variants in the alternate complement pathway, as compared to persons with low-risk variants. This gave scientists a way to differentiate specific effects of genotype on disease characteristics.

Using this model, researchers were able to find two drugs from a library of over 1,200 that were able to lessen retinal pigment epithelium cells atrophy drusen formation. One is aminocaproic acid, which blocks the complement pathway outside cells. The other is L745, which stops the complement induced inflammation inside the cell indirectly by way of inactivation of the dopamine pathway.

The AREDS2 iPSC-derived RPE cells are available through a repository managed by the New York Stem Cell Foundation. For more information, visit https://nyscf.org/research-institute/repository-stem-cell-search/.

Watch Out for Drusen
Scientists at the University of Colorado School of Medicine are presenting evidence linking drusen formation with extracellular vesicles and AMD. The extracellular vesicles are compounds secreted by cells.

Research shows that the retinal pigment epithelium cells release exosome that have both normal proteins and proteins associated with drusen. Under stressful conditions, researchers found that the retinal pigment epithelium cells release drusen-associated proteins about 20 times more, which can be potential marker for AMD.

This research demonstrates that when retinal pigment epithelium cells are exposed to an environment similar to that which leads to AMD, they respond with a big increase in the release of drusen related proteins by way of the exosomes. Scientists have been looking for the origins of drusen-associated proteins as it relates to AMD and now this biomarker can be found in samples of blood, tears, saliva or urine.

Knowing that the extracellular vesicles are releasing drusen-associated proteins offers an opportunity for diagnostic and therapeutical approaches that will lead to better treatments for AMD. In particular, before the development of geography atrophy, which is a later stage of dry AMD. In addition, there could be tools to target and modulate the exosome release and protect the cells from drusen accumulation.

“If we understand how drusen form and what cells or mechanisms contribute to their formation, we may be able to control the formation of drusen and slow down or even, perhaps prevent, some of the pathological events leading to AMD,” said Valeria Canto-Soler, PhD one of the scientists involved in the study.

Source:Sources:
https://www.nei.nih.gov/about/news-and-events/news/nih-researchers-identify-potential-amd-drugs-stem-cell-based-research-tool

https://news.cuanschutz.edu/medicine/cu-researchers-provide-first-evidence-linking-extracellular-vesicles-with-drusen-formation-and-amd

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