Lipofuscin-Mediated Endoplasmic Reticulum Stress in the Pathogenesis of Macular Degeneration
As retinal pigment epithelium (RPE) gets old, it accumulates a lot of lipid bisretinoids (LBs). Above a certain threshold, or after exposure to light, LBs become toxic and may induce cell death. Many groups have previously identified mechanisms by which LBs damage the RPE. These studies, however, did not provide us with a method to clear LBs or alleviate their harmful effects. Working with cultures of RPE cells and synthetic LBs, we found a novel mechanism by which LBs kill RPE cells. This mechanism seems to be central to LB toxicity and is amenable to inhibition with drugs, as already we have identified two chemical compounds that fully prevent RPE cell death by LBs. Interestingly, some of these drugs are being tested for the treatment of neurodegeneration in Parkinson’s and Alzheimer’s disease. In the current project, we propose to fully characterize this new damaging mechanism, prove that it contributes significantly to LB-induced retinal degeneration in the eye, and test whether drugs that block this mechanism can prevent blindness in an animal model of AMD.
In the United States, age-related macular degeneration (AMD) is the foremost cause of irreversible vision loss in people over 70 years of age. Several factors contribute to the selective failure of this small area in the center of the retina that is responsible for humans’ most sharply focused vision. Among them: the macula contains by far the highest density of photoreceptors; it is irrigated only from underneath through choroid blood vessels; and it’s exposed to the highest levels of light. Light triggers visual impulses but also promotes the formation of all-trans-retinal (ATR), a form of vitamin A that is very toxic and needs to be recycled to prevent its self- conversion into dimeric forms, called lipid-bisretinoids (LBs). LBs formed in the photoreceptors are dumped into the retinal pigment epithelium (RPE) which is in charge of keeping the retina clean. As RPE gets old, it accumulates a lot of LBs. Above a certain threshold, or after exposure to light, LBs become toxic and induce RPE cell death and subsequent photoreceptor cell death. Many groups have previously investigated mechanisms by which LBs damage the RPE. The problem is, these studies did not provide us with a method to clear LBs or alleviate their harmful effects. Working with cultures of RPE cells and synthetic LBs, we found a novel mechanism by which LBs kill RPE cells. The distinctive detail here is that this mechanism is amenable to drug therapy, as already we have identified two chemical compounds that fully prevent RPE cell death by LBs. Interestingly, some of these drugs have shown positive effects for the treatment of neurogenerative diseases, such as Parkinson’s and Alzheimer’s disease. In the current project, we propose to fully characterize this new damaging pathway, and test whether by targeting this pathway we can prevent blindness in animal models of LB-driven retinal disease.
About the Researcher
Dr. Marcelo Nociari is an assistant professor of ophthalmology at the Dyson Research Institute at Cornell University. He earned a BA in chemistry, a BS in biochemistry and a PhD in immunology from the University of Buenos Aires (Argentina). During his postdoctoral training at Cornell University Medical College, he acquired extensive experience in the immunobiology of aging, chronic inflammatory diseases and innate immunity. As a postdoctoral associate and later as a young faculty member, he identified a central innate immune cascade involved in the activation of adaptive immune response against adenoviral vectors used in gene therapy. For the past six years, Dr. Nociari and Dr. Boulan (co-principal investigator on this BrightFocus project) worked together to develop a treatment against dry AMD and other lipofuscin-driven retinal disorders. They currently are pursuing two complementary pharmacological approaches: (i) developing drugs capable of removing lipofuscin from RPE (BrightFocus award 2013-15); (ii) targeting lipofuscin-elicited damaging cascades to prevent chronic inflammation and RPE cell death (BrightFocus award 2016-18). Dr. Nociari uses animal models, cell culture, and biochemical approaches to study from different perspectives the impact that lipofuscin accumulation has in retinal disease. In addition to the BrightFocus awards, Dr. Nociari has received a number of grants from NIH.
The financial support by BrightFocus Foundation has been instrumental for the identification of drugable targets in dry AMD and related lipofuscin-driven retinal disorders.
Specifically, my first BrightFocus award (2013-2015) allowed us to identify a novel set of compounds, the beta-cyclodextrins, as potential candidates to clear lipofuscin from RPE. We are now developing nanoparticle-based technologies that will specifically target and release beta-cyclodextrins to the RPE in the eye. Furthermore, during this period, we have also characterized functionally and morphologically the animal model of lipofuscin-driven retinal disease, which is central for efficacy studies. And now, the current BF support (2016-2018) will allow to investigate the therapeutic potential of a new set of drugs that interfere with a cell death mechanism initiated by lipofuscin that have been shown to be important for other neurodegenerative disorders.
We would like to express our sincere gratitude to BrightFocus Foundation and its donors for their generous support of our research and to the ways in which it has furthered Dr. Nociari's scientific career development. In addition, we restate our commitment to developing effective treatments that will benefit patients with AMD and other lipofuscin-driven retinal diseases.
First published on: July 19, 2016
Last modified on: September 7, 2018