Use of Patient-Derived Cells to Test Compounds that Will Reverse Exfoliation Glaucoma

Audrey Bernstein, PhD
SUNY Upstate Medical University (Syracuse, NY)

Co-Principal Investigators

J. Mario Wolosin, PhD
Icahn School of Medicine at Mount Sinai
Year Awarded:
Grant Duration:
July 1, 2016 to September 30, 2018
Award Amount:
Grant Reference ID:
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Award Region:
US Northeastern
Audrey Bernstein, PhD

Autophagic Dysfunction in Exfoliation Glaucoma


In exfoliation syndrome (XFS), which can lead to glaucoma, the eye starts accumulating “white fluff” deposits composed of protein aggregates. The aggregates eventually block the exit of fluid from the eye, causing a buildup of pressure that can lead to blindness. We have discovered that cells obtained from XFS eyes have a dysfunction in the cellular machinery that degrades protein aggregates. We hypothesize that this dysfunction leads to an accumulation of “cellular trash” that becomes toxic to the cell. In this project, we will test methods to accelerate degradation of this cellular waste to improve the health of XFS cells.

Note: This grant was transferred from the Icahn School of Medicine at Mount Sinai to SUNY Upstate Medical University on July 1, 2017.


Our goal is to reverse the effects of exfoliation syndrome (XFS), the leading identifiable cause of open-angle glaucoma.  

Like recent work in studies of several other age-related diseases, such as age-related macular degeneration (AMD) and Alzheimer’s disease, our lab has found that XFS cells have a dysfunction in the cellular machinery that would normally degrade protein aggregates (autophagy and lysosomes) and in the organelle that produces the energy needed for the cellular degradation (mitochondria). Our hypothesis is that these defects play a role in generating the accumulation of cellular waste that becomes toxic. We are growing cells from tissue derived from XFS patients who have undergone glaucoma surgery to relieve pressure in the eye. These cells are called tenon fibroblasts. Since one of the major challenges of XFS research has been a lack of model systems for experimental purposes, our patient-derived cells provide a wealth of opportunity to identify critical pathways that are disrupted in XFS-affected cells and to use these patient cells to screen for molecules that can reverse lysosomal and mitochondrial dysfunction.

Specifically we will utilize the tenon fibroblast model system to 1) distinguish the proteomic profiles specific to XFS cells and the autophagic defect; 2) test that the autophagic defect in these cells is the reason for the build-up of toxic aggregates as we have hypothesized and 3) screen these patient-derived cells with autophagy-stimulating drugs to identify compounds that may reverse the dysfunction. Together these approaches will drive towards our goal of reversing XFS pathology in patients.

About the Researcher

Audrey Bernstein, PhD, is an associate professor in the Departments of Ophthalmology and Pharmacology and Systems Therapeutics at the Icahn School of Medicine at Mount Sinai, New York, NY. Her post-doctoral training was in the field of ocular wound healing.

Our work is focused on two clinically important ocular disorders: scarring and glaucoma. Our studies focus on the involvement of abnormal protein accumulation in both of these ocular pathologies. Specifically, we have elucidated novel intracellular ubiquitin-mediated degradation pathways that control cell-surface integrin expression and subsequent fibrotic growth factor (TGFb) signaling and scarring in the eye. Silencing of specific genes in this pathway prevents scarring and promote regenerative healing.

In exfoliation glaucoma, the leading identifiable cause of open-angle glaucoma, accumulation of protein aggregates in the eye leads to elevated intraocular pressure and subsequent glaucoma. We have discovered that a significant lysosomal/autophagic and mitochondrial defect defines primary cells isolated from the eyes of XFS patients. Our studies suggest that these age-related dysfunctions may be an underlying cause of this blinding disease

 In both studies, the use of patient-derived primary cells and organ culture, quantitative confocal microscopy, histology, flow cytometry, lentivirus technology, and genetic screening are utilized to reveal new therapeutic targets to prevent vision loss. Dr. Bernstein’s serves as an ocular expert reviewer for several study sections including the National Eye Institute (NEI), The U.S. Department of Veteran’s Affairs, the Medical Research Council (MRC) in the UK, and The Glaucoma Foundation. Her research has been supported by NEI, Research to Prevent Blindness, The Glaucoma Foundation, BrightFocus Foundation, and the Moise and Chella Safra Foundation, as well as private donations.  

Personal Story

Dr. Robert Ritch at the New York Eye and Ear, a renowned glaucoma specialist, brought my collaborator, Dr. J Mario Wolosin and I, into this important project. Collectively, our deep knowledge of exfoliation glaucoma and the cellular mechanisms that lead to disease, as well as Dr. Ritch’s access to formally discarded human tissue and our expertise in growing and analyzing cells from tissue samples has yielded a very productive translational collaboration.  We are extremely excited about the promise of our research. Our goal is to harness what has already been discovered in neurodegenerative diseases that parallel our research on XFS glaucoma and adapt those findings to identify cellular pathways that can be targeted to reverse XFS disease in patients. We are grateful to the BrightFocus donors for their generous and crucial support of our research to cure this blinding disease.

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