Looking Beyond the Retina to the Biology of AMD
Macular Degeneration Research at ARVO 2019
Macular degeneration is a blinding disease that damages central vision by destroying the nerve cells of the macula, at the very center of the retina. Particularly with the most common type, called age-related macular degeneration (AMD), this gradual neurodegeneration can take years.
And even though AMD slowly damages light-sensing neurons, many other cell types appear to be involved in the disease process. At ARVO 2019, BrightFocus grantees shared a wealth of discoveries about key players involved in macular degeneration. They describe the retina as a dynamic and changing environment where crosstalk among cells and cross-currents of immune activity can have positive or negative consequences for AMD.
In his ARVO 2019 talk and poster, Daniel Saban, PhD, a 2017-19 Macular Degeneration Research (MDR) grantee from Duke University, described how the resident immune cells of the brain and retina, called microglia, reside in microenvironments, called “niches,” in the subretinal space, and then migrate to the damaged retinal pigment epithelium (RPE), a layer of cells that helps to feed and maintain retinal neurons. The microglia then try to protect the RPE from further damage by turning on genes involved in antioxidant functions and other protective pathways, and turning off genes involved in negative immune response pathways.
However, Dr. Saban and colleagues have discovered that the behavior of microglia cells may vary, depending on their location and circumstances. In an animal model, they detected differences in the response of microglia recruited from different parts of the retina. These findings were recently published (O’Koren et al, Immunity, 2019). Studies such as Dr. Saban’s enhance our understanding of immune cell behavior in AMD and open up new ideas for targeted therapies. [ARVO 2019 Abstracts No. 5640 and 985.]
Dr. Edwards thinks that these changes to MC location and function are driven by signaling that causes MCs to take over and “fill in” where they detect dysfunction. While this response may initially be helpful to other retinal cells, MC remodeling could also harm the retina and impair treatment attempts. She thinks the same process is happening in geographic atrophy (GA), a late-stage form of dry AMD. (ARVO 2019 Abstract No. 4388)
Kick-Starting an Immune Response
To have one’s presentation labeled as a “Hot Topic” by the ARVO Program Committee, is a special honor indicating that it represents some of the newest and most innovative thinking in the field.
In the case of Dr. Ildefonso’s talk, finding treatments for GA also happens to be one of the most pressing current needs in the macular field. Like wet AMD, GA also kills retinal cells and causes vision loss, but without the overgrowth of fragile, leaky blood vessels seen in wet AMD. And whereas wet AMD can be treated with drug injections, GA has no treatments at this time.
AMD develops in part because the delicate nerve cells of the retina, and the tissue layers that support them, become stressed over decades of use. Gradually retinal conditions deteriorate, and Dr. Ildefonso and colleagues had the idea to test what would happen if they kick-started an immune response. To do so, they injected a low-dose of lipopolysaccharides (LPS), or large molecules found in the outer membrane of gram-negative bacteria, in animal models to simulate low-level inflammation. To their surprise, activating the innate immune response in this way yielded short-term protection to both the retina structure and its response to light. “Understanding how this activation of the systemic immune response protects the retina could lead to the identification of therapies that may help slow AMD,” Dr. Ildefonso and his colleagues concluded. [ARVO 2019 No. Abstract 989]
Looking at Other Cellular Players
In an ARVO 2019 poster, Dr. Singh further solidified that hypothesis, reporting that both localized cell signaling from the RPE and choroid, as well as factors carried in blood serum, alter cell activities in ways that contribute to drusen formation [ARVO 2019 Abstract No. 1227].
In a talk, described how a rare inherited form of retinal degeneration impairs the cross-talk between photoreceptors (PR), which are the light-sensing neurons of the retina, and the retinal pigmented epithelium (RPE), a layer of cells that provide their life support. This can lead to RPE dysfunction. [ARVO 2019 Abstract No. 4763].
In summary, BrightFocus-funded research at ARVO provided new insights about what’s going on at the cellular level in and near the retina during macular degeneration. Armed with these insights, other BrightFocus-funded researchers are discovering new treatments, including neuroprotection, ie, ways to nourish and defend retinal cells from damage. More about that in other reports from ARVO 2019.