Jason Miller, MD, PhD
University of Michigan Health Kellogg Eye Center
Congratulations to Dr. Miller from the University of Michigan Health Kellogg Eye Center, who is the 2021 recipient of the Retina Society’s prestigious Raymond R. Margherio Award! Dr. Miller’s research program seeks to establish retinal pigment epithelium (RPE) culture models for dry age-related macular degeneration (AMD) as a platform for testing therapeutic models. He discussed his groundbreaking research looking at ways to improve lipofuscin clearance through autophagy by the RPE at the Retina Society Meeting in Chicago.
Can you tell our readers about your study?
We think about AMD as a disease of lipid accumulation. Every day, the RPE takes up enormous amounts of lipid, both via lipoprotein particle uptake from the choroid, and via phagocytosis of photoreceptor outer segments. This daily lipid load leads to the temporary accumulation of lipid droplets in RPE, but permanent accumulation of intracellular lipid droplets is not a prominent feature of AMD. We hypothesize that the RPE, even in old age and in patients with AMD, makes active decisions about how to dispose of its daily intracellular lipid load. If it decides to degrade the lipid, that produces energy and metabolites that are beneficial for both the RPE and overlying photoreceptors. In contrast, if the degradative capacity of the RPE is overwhelmed, the RPE may secrete its excess lipid in lipoprotein particles. We know the RPE is capable of prodigious amounts of lipoprotein secretion, and we also know that the pathologic hallmarks of AMD, extracellular drusen and reticular pseudodrusen, are both lipid rich and derive largely from lipoprotein accumulation. Thus, if the RPE decides to secrete its lipid rather than degrade it, then there will be an increase in drusen and reticular pseudodrusen deposition. We are therefore interested in ways to steer the RPE towards degrading lipid rather than secreting it as a therapeutic approach to AMD.
Tell us more about the details of this novel therapeutic approach?
One mechanism used to degrade lipid droplets in cells is autophagy. Among other functions, autophagy involves the engulfment of lipid droplets by a vesicular structure called an autophagosome. Once the autophagosome bites off lipid, it delivers the lipid to the digestive enzymes present in the lysosome. The resulting release of fatty acids can then be degraded further in the mitochondria to produce energy. Unfortunately, the major mechanism to activate autophagy is the inhibition of an enzyme called mTOR, which is a master regulator of cell energy. Clinically, we inhibit mTOR when using sirolimus, which is used as an intravitreal injection in uveitis. Sirolimus failed in a randomized controlled trial for inhibiting GA progression, and we found that mTOR inhibition in human RPE cells induces several unwanted effects, including a loss of the RPE’s phagocytic capacity and a decrease in the RPE’s outer-retinal barrier function. Thus, we tested many compounds for their ability to induce autophagy in the RPE via mechanisms other than inhibition of mTOR. We found an FDA approved compound, flubendazole, that can induce autophagy in the RPE in an mTOR-independent way, is non-toxic, and improves the RPE’s ability to degrade lipid into beneficial energy rather than secrete the lipid into drusen and reticular pseudodrusen-promoting lipoprotein particles. Incidentally, this compound is also capable of clearing lipofuscin in the RPE, since autophagy is known to clear unwanted intracellular debris. Improved clearance of lipofuscin could be helpful in Stargardt’s.
What are your next steps?
We are taking a two-pronged approach. First, we are testing many other compounds for their ability to induce RPE autophagy in a non-toxic and mTOR-independent way, and then determining if they improve the lipid handling profile of the RPE (less lipid secretion, less lipofuscin buildup, more lipid degradation). In particular, we have found that several VEGF receptor kinase inhibitors, which should block choroidal neovascularization, also induce autophagy in an mTOR-independent fashion. This suggests we could identify compounds that simultaneously prevent CNVM and treat dry AMD. Second, once we have identified a core set of candidates, we plan on taking our studies from human RPE culture into animals for safety and efficacy studies.