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RESEARCH GRANTS 2019-2025 Message

The Glaucoma Foundaon is dedicated to improving the lives of people with glaucoma. The Foundaon works to encourage and support basic and applied research in glaucoma with a goal of preserving and restoring vision. The Foundaon oers grants to researchers striving to improve the lives of glaucoma paents through novel innovaons and scienc advances. Beginning in 2024, one-year grants of up to $75,000 will be made in the areas of Exfoliaon Syndrome and Exfoliaon Glaucoma, Pressure Independent Mechanisms of Glaucoma, Neuroprotecon, and the Genecs of Glaucomas that aect people under the age of 40. Preference will be given to transformaonal research projects with high clinical signicance.

2019 RESEARCH GRANTSUnraveling the Proteolyc Landscape Regulang LOXL1 Implicaons in the Development of Pseudoexfoliaon Syndrome Principal Invesgator: Fernando Rodriguez Pascual, PhDCentro de Biologia Molecular “Severo Ochoa” (CSIC/UAM)Madrid, SpainWhile precise pathogenesis of PEX syndrome remains unknown, the idencaon of genec variants in the LOXL1 gene strongly associated to the disease has opened new avenues for the invesgaon on its molecular causes. The protein product of the LOXL1 gene belongs to the lysyl oxidase (LOX) family, a group of enzymes contribung to build the extracellular matrix (ECM) by promong the covalent associaon (cross- linking) of elasn and collagens. In parcular, LOXL1 plays an important role in the formaon of elasc bers, the ECM scaold mostly imparng elascity to animal ssues, an observaon very consistent with its idencaon as an integral part of the PEX deposits.With the support of a previous grant from TGF, we iniated a line of research aiming to invesgate the proteolyc processing of LOXL1 and its potenal implicaons in the development of PEX syndrome. Far from being completed, our results provide a glimpse of the complexity of the proteolyc landscape regulang LOXL1 expression and acvity, ancipang excing ndings potenally important for the development of PEX syndrome. Here we apply for a renewal of the support from TGF to accomplish the characterizaon of LOXL1 proteolyc regulaon and to invesgate its pathological relevance in the development of PEX syndrome.

2019 RESEARCH GRANTSGrowth Dierenaon Factor 15 Levels in Pseudoexfoliaon Glaucoma Principal Invesgator: Rajendra Apte, MD, PhDWashington University, St. Louis, MOThere are several kinds of glaucoma, all of which can lead to the death of cells in the eye that send visual informaon to the brain. Prevenng these cells from dying is an important part of the treatment for glaucoma. However, it can be dicult for physicians to idenfy which paents are at highest risk of developing glaucoma, or having their glaucoma get worse over me.Finding a marker, such as a protein in the eye whose presence might predict whether glaucoma will get worse, would make it possible for physicians to beer determine whether a paent should have surgery or another treatment. This project will study a protein called ‘growth dierenaon factor 15’ (GDF-15), which is associated with renal stress in rodents and humans. By measuring the levels of this protein in human paents with glaucoma before and aer surgery, we hope to understand whether there is a relaonship between GDF-15 levels in the eye, the severity of glaucoma, and success of glaucoma surgery. If high GDF-15 levels are linked with more severe glaucoma, it could be used as a marker to help determine treatment for paents at the highest risk of developing severe glaucoma.“With support from TGF, we are investigating whether a protein called Growth Dierentiation Factor-15 is a molecular biomarker for pseudoexfoliation (PXG). ese human pilot studies in patients with PXG can only be executed because of this generous grant support. We are analyzing the data and hope to publish our ndings before the end of the year.”

Metabolomic Analyses of Aqueous Humor of Pseudoexfoliaon GlaucomaPrincipal Invesgator: Sanjoy K. Bhaacharya, M. Tech, PhDBascom Palmer Eye InstuteUniversity of Miami Miller School of Medicine, Miami, FLWe will idenfy the small molecules in the clear uid of the front part of the eye termed aqueous humor. These small molecules are involved in all day-to-day funcons of biological ssues in the eye. This analysis will show a dierence in small molecules between pseudoexfoliaon glaucoma and normal eyes. Their addion (for example the molecules that provide energy) or removal (for example known toxic molecules) may be early intervenon strategies for treang pseudoexfoliaon glaucoma.2019 RESEARCH GRANTS“is grant has supported our critical experiments of metabolite proling and machine learning, and opened up the prospect for an extramural federal grant to fully investigate the initial mechanisms leading to deposit formation.”

New Understanding from Mouse Lines with Features of Pseudoexfoliaon SyndromePrincipal Invesgator: Yong Yuan, PhDCollege of Medicine, University of Cincinna, Cincinna, OhioPseudoexfoliaon syndrome is the most idenable cause of open-angle glaucoma. Animal models are crical tools for nding the cause of the disease and for tesng potenal treatment regimens. Currently, no animal model is available that can recapitulate the symptoms of this disease. We found features of pseudoexfoliaon syndrome in several mouse lines with genec defects aecng cellular funcons. The objecve of this proposal is to nd what is the common cause of the disease among these mouse lines. New knowledge obtained from this study will lead to a beer understanding of the disease as well as new strategies for combang the disease.2019 RESEARCH GRANTS“As a new investigator to the glaucoma eld, I am blessed to have the trust and the support from e Glaucoma Foundation in the form of grant awards and intellectual support at the ink Tank meetings. e grant helped me to collect critical data for a competitive NIH grant.”

Abnormal Extracellular Matrix Homeostasis of Trabecular Meshwork Cells in Pseudoexfoliaon Syndrome and Glaucoma Principal Invesgator: Katy Liu, MD, PhDDuke OphthalmologyDuke University School of MedicinePseudoexfoliaon glaucoma is the most common glaucoma with an idenable cause. However, there is no targeted treatment for pseudoexfoliaon glaucoma. The trabecular meshwork lies within the drain of the eye, and it has the highest resistance to oulow of eye uid or aqueous humor. Many sciensts theorize that the trabecular meshwork cells put down dysfunconal surrounding matrix, or extracellular matrix, which provides support for the cells. There is no suitable model to study the extracellular matrix of trabecular meshwork cells. For the rst me, we have grown trabecular meshwork cells from pseudoexfoliaon donors. This powerful tool will allow us to determine alteraons the trabecular meshwork extracellular matrix, and we have preliminary data to support this idea. We will also determine the eect of extracellular matrix on the biomechanical properes of trabecular meshwork cells, or the cell’s rigidity, which directly aects resistance to oulow of aqueous humor. This study is crical to further our understanding the role of the extracellular matrix in the mechanism of pseudoexfoliaon disease. With this knowledge, the extracellular matrix could be targeted by future drug and medical therapies. 2019 RESEARCH GRANTS

2019 RESEARCH GRANTSRole of LOXL1 Acvity in TGF-Beta 1-Mediated Fibrosis in the Convenonal Oulow PathwayPrincipal Invesgator: Heather Schmi, BS, MS, PhD Duke University, Durham, NC The proposed research is designed to invesgate the regulatory role of the LOXL1 protein that is associated with risk of pseudoexfoliaon glaucoma. We are interested in how LOXL1 acvity contributes to elevaon in eye pressure that is typical of pseudoexfoliaon glaucoma. Specically, we will invesgate the relaonship between LOXL1, a signaling molecule called TGF-beta 1 (Transforming Growth Factor) and eye pressure, using a mouse model. TGF-beta 1 is oen elevated in eyes of people with pseudoexfoliaon glaucoma, and it is known to induce “scarring” that causes elevated eye pressure. Results from this project will provide a beer understanding of disease mechanism and may lead to targeted clinical intervenons for pseudoexfoliaon glaucoma.“is grant has provided critical funding for technician salaries, biological materials, and animal care to complete these experiments. We believe that the results of this study will give us new insight into the role of LOXL1 in TGF-beta 1-mediated brosis in pseudoexfoliation glaucoma, potentially qualifying LOXL1 as a suitable drug target for pseudoexfoliation glaucoma treatment.”

2020 RESEARCH GRANTSIdenfying Glaucoma Risk Alleles in the LOXL1 Promoter Using a Massive Parallel Promoter AssayPrincipal Invesgator: John H. Fingert, PhDUniversity or IowaExfoliaon syndrome is a disease that causes accumulaon of brillar material (exfoliaon material) in ssues throughout the body, including the eye. Paents with exfoliaon syndrome are at high risk for glaucoma and vision loss, thus exfoliaon syndrome is a public health problem. The specic causes of exfoliaon syndrome are unknown, but hereditary is important. The genec basis of exfoliaon syndrome is complex and involves the interacon of many genec and environmental factors. Seven genec risk factors have been discovered, and one of these genes, LOXL1, is a potent risk factor for disease. In this applicaon, we propose experiments to determine the mechanism by which the LOXL1 gene confers risk for exfoliaon syndrome. Our hypothesis is that dozens of dierent genec mutaons together cause an abnormal amount of LOXL1 protein to be produced in the eye, which in turn damages the drainage structures of the eye and leads to glaucoma. With our proposal we will idenfy dozens of mutaons that alter LOXL1 producon in the eye using a DNA sequencing technique known as BiT-STARR-seq. The overall goal of these experiments will be to idenfy the specic cause of exfoliaon syndrome at the molecular level (i.e. LOXL1 gene mutaons).

THE BARRY FRIEDBERG AND CHARLOTTE MOSS GRANT AWARDAn-Fibroc Potenal of All-Trans Renoic Acid in Pseudoexfoliaon Syndrome and GlaucomaPrincipal Invesgator: Ursula Schlötzer-Schrehardt, PhDUniversity of Erlangen-NürnbergThe causes underlying the development of pseudoexfoliaon syndrome and its associated glaucoma, which is the most common type of secondary open angle glaucoma associated with a high risk of blindness, are not fully understood, and there is no specic treatment. This project addresses the current need for a beer understanding of the mechanisms of PEX pathogenesis and idencaon of therapeuc targets. It proposes to test the hypothesis that impaired renoic acid signaling is causally involved in the abnormal broc matrix process. It is further suggested that compounds smulang renoic acid signaling have a potenal to reverse the adverse broc eects of disease. It is ancipated that the ndings will idenfy novel pathomechanisms involved in the development of PEX glaucoma and advance the development of novel therapeuc approaches for the treatment of pseudoexfoliaon syndrome and glaucoma. Dr. Schlötzer-Schrehardt is a member of TGF’s Scienc Advisory Board. She is a professor at the University of Erlangen - Nürnberg’s Department of Ophthalmology where she has been cited as the world’s leading expert on the pathogenec mechanisms causing PEX and lauded for her tremendous contribuons to our knowledge of the cellular and molecular mechanisms that cause this disease.

Role of IGFBPL1 on Renal Ganglion Cell Survival in an IOP-independent Injury ModelPrincipal Invesgator: Kin-Sang Cho, PhDSchepens Eye Research InstuteGlaucoma is a globally unmet medical challenge because of its prevalence, devastang consequences and lack of eecve treatment. The disease leads to progressive loss of renal ganglion cells and vision. Our recent study idened a protein called insulin-like growth factor binding protein like-1 (IGFBPL1) that is a novel regulator of renal ganglion cells survival and nerve growth. Progressive loss of renal ganglion cells and their axons in the opc nerve is a characterisc feature of glaucoma, leading to vision loss. We recently observed lack of IGFBPL1 in mice exhibits progressive degeneraon of renal ganglion cells, which mimics the pathogenesis of IOP-independent glaucoma. It suggests that IGFBPL1 is a key player to maintain RGC survival in the adult. The proposed study will invesgate the regulatory networks of IGFBPL1 and the long-term eect of IGFBPL1 on the survival in a IOP-independent glaucoma model. Aer compleon of the proposed studies, we ancipate uncovering novel molecular targets for glaucoma therapy.2020 RESEARCH GRANTS

Renal Organoids to Study Disease Progression and Intervenon in GlaucomaPrincipal Invesgator: Miriam Kolko, MD, PhDUniversity of CopenhagenGlaucoma is characterized by the progressive loss of the renal ganglion cells (RGCs), and while IOP clearly plays a role, several lines of research have indicated that dysfuncon of the Müller glia (MG) play a key role in the pathophysiology.We hypothesize that vulnerability to RGC loss depends on MG􀂶s ability to protect theRGCs and that MG dysfuncon due to glaucoma will aect the essenal partnership between RGCs and the MG. We will look at two paents’ groups, denoted normal tension glaucoma (NTG) and ocular hypertension (OHT). In NTG paents, IOP is within the normal range, but paents sll experience glaucomatous RGC loss. We assume that NTG paents may have a specic MG dysfuncon leading to RGC loss. In contrast to NTG paents, paents with OHT have increased IOP but no evidence of glaucomatous damage. These paents may have a resistance due to a sustained healthy MG and are therefore able to withstand the high IOP. Unlike NTG paents, paents with OHT have increased IOP but no evidence of glaucomatous injury. They may have a resistance due to connued healthy MG and therefore are able to withstand the high IOP. Our hypothesis is that we can detect new neuroprotecve targets from MG derived from OHT paents as well as further idenfy both toxic and neuroprotecve targets in RGCs that have been exposed to MG from NTG or OHT paents, respecvely.2020 RESEARCH GRANTS

Schlemm’s Canal Catheterizaon a n d S u b s t a n c e D e l i v e r y i n L i v e M o n k e y sPrincipal Invesgator: Paul L. Kaufman, MDUniversity of Wisconsin MadisonGlaucoma is the leading cause of irreversible blindness. Its prevalence increases with age. Lowering pressure inside the eye is crical to glaucoma therapy, and slows progression of opc nerve damage and visual loss. Self- administered eye drops ulize various drugs that enhance uid oulow from or decrease uid formaon by the eye, reducing eye pressure. Most paents will require several classes of drop therapy, each self-administered one to three mes daily. Unfortunately, paent adherence to self-administered drop regimens is poor, because of age-related inrmies and the complexity of medical regimens for co-exisng condions. In live monkeys, we will inject viruses carrying genes that enhance uid oulow into the small drainage channel (Schlemm’s canal) that encircles the front part of the eye, permanently reducing the ow resistance of the major oulow pathway, reducing the viral load, avoiding o-target local and systemic adverse side eects, assuring consistent therapeuc ecacy, and relieving the paent’s physical and psychological burden We have designed and fabricated the ny catheters, mastered the microscopic injecon technique, constructed virus-gene vectors that work in cells and in organ-cultured monkey eyes, and are ready to move into live monkeys (this project) and then hopefully into human clinical trials.2021 RESEARCH GRANTS

DNA Methylaon and RGC Degeneraon in GlaucomaPrincipal Invesgator: Shahid Husain, PhDUniversity of South CarolinaGlaucoma is the second leading cause of blindness worldwide. Nearly 80 million people worldwide are believed to have glaucoma, including an esmated 3 million in the USA. Approximately 120,000 people are blinded by glaucoma accounng for 9-12% of all cases of blindness. Vision loss is caused by damage to the opc nerve, which connects eye to the brain for image formaon and recognion. In most cases of glaucoma, vision loss is coincident with elevated eye pressure. This pressure imbalance in the eye over a long period of me causes degeneraon of eye neuron, which ulmately leads to the blindness. During the progression of glaucoma, numerous factors including epigenecs play crucial role. Chemical reacons with the help of enzymes can modify DNA. Once DNA is chemically modied it will become ghtly packed and reduces it acvity for the producon of certain benecial factors such as neurotrophins. Neurotrophins are essenal components for the neuron of healthy eye. When DNA is ghtly packed it will not allow machinery to produces neurotrophins, as a result neurons will be deprived of neurotrophins and start to degenerate. Once sucient number of neurons are degenerated, it will lead to the blindness, as seen in glaucoma.LINDA AND KENNETH MORTENSON GRANT AWARD

Mouse Strain Specic Dierences in Intracranial Pressure and Suscepbility to GlaucomaPrincipal Invesgator: Colleen M. McDowell, PhDUniversity of Wisconsin MadisonGlaucoma is a silent, underdiagnosed, costly and debilitang disease and the only treatment opons for the disease include reducing elevated pressure within the eye. However, paents are somemes resistant to current established treatments and it is crucial to idenfy therapies and develop new treatments for glaucoma that can directly save the visual neurons from dying. We will ulize mouse models to study changes in pressure occurring on the eye neurons from both inside the eye and from the brain side of the eye in glaucoma to idenfy new protecon therapies.2021 RESEARCH GRANTS

2021 RESEARCH GRANTSTargeng Neuronal NAD Producon Through NMNAT2 Acvity for Neuroprotecon in GlaucomaPrincipal Invesgator: Pete A. Williams, PhD St Erik Eye HospitalOur research program has idened metabolic dysfuncon in the rena and opc nerve in experimental glaucoma animals and human glaucoma paents. We have discovered that an important molecule, ‘NAD’, declines in the rena and opc nerve during glaucoma, and increasing NAD levels using niconamide (a form of vitamin B3 and a precursor to NAD) prevents glaucoma in animals. Niconamide is also low in the blood of glaucoma paents and we have now demonstrated that niconamide treatment can increase visual funcon in glaucoma paents. NAD producon is an ideal target for drug discovery for glaucoma and we have now generated a number of novel drugs that target these processes. This research program will further these studies by designing and tesng new NAD-generang drugs with an aim to raise NAD in the rena and opc nerve. This will provide novel glaucoma treatments that are not reliant on, but can be used in combinaon with, exisng pressure lowering treatments.

THE KUMAR MAHADEVA GRANT AWARD 2021 - 2023Uncovering the Potenal of Pericytes as Therapeuc Targets for GlaucomaPrincipal Invesgator: Adriana Di Polo, PhD University of MontrealRenal ganglion cells (RGC), the neurons that die in glaucoma, are metabolically acve and require a precise regulaon of blood supply to meet their high oxygen and nutrient demand. The vascular theory of glaucoma proposes that insucient blood ow contributes to RGC neurodegeneraon. Glaucoma paents suer from vascular decits including decreased blood ow in the rena and opc nerve, reduced vessel caliber, and capillary defects. Notably, vascular autoregulaon and icker-induced neurovascular coupling, a key process that matches blood ow to the metabolic demand of acve neurons, are severely compromised in this disease. However, the cellular mechanisms underlying vascular dysfuncon in glaucoma and their impact on neuronal damage are currently unknown. Pericytes, the ensheathing cells that wrap around capillary walls, have emerged as key regulators of microcirculatory blood ow and neurovascular coupling. Pericytes are centrally posioned within the neurovascular unit, contain contracle proteins, and respond rapidly to neuronal smulaon. The renal microvasculature is rich in pericytes, with >90% pericyte coverage in human renal capillaries. We recently reported that inter-pericyte tunneling nanotubes (IP-TNTs), ne tubular processes that connect renal pericytes on distal capillary systems, are essenal for neurovascular coupling in the rena. These ndings were published in the impacul journal Nature (2020) and were lauded as crically important by the scienc community at large. Despite this, the role of pericytes and IP-TNTs in vascular dysregulaon in glaucoma has not been invesgated. To ll this knowledge gap, we recently developed a novel two-photon laser scanning microscopy (TPLSM) technique to visualize renal pericytes and single capillary blood ow in living mice).

Human Stem Cell Derived RGCs for Invesgang Nrf2 Acvaon as Neuroprotecon Approach in GlaucomaPrincipal Invesgator: Arupratan Das, PhDIndiana UniversityProgressive loss of renal ganglion cell (RGC) neurons of opc nerve causes glaucoma leading to complete blindness. Currently, over 3 million Americans are suering from glaucoma without any cure. Lowering high eye pressure provides temporary relief but without the cure. Till date no therapy is available for RGC neuroprotecon in glaucoma. Thus, there is a crical need to develop therapy to protect the RGC neurons. Studies in glaucoma paents’ rena and in animal models of glaucoma have widely found presence of elevated reacve oxygen species (ROS) which are toxic chemicals and cause oxidave stress, potenally leading to RGC death in glaucoma. Mitochondria are the energy source for cells, but damaged mitochondria are the primary source of toxic ROS chemicals. In healthy cells, ROS are cleared by acvaon of Nrf2 transcripon factor. Several of Nrf2 acvators are under FDA clinical trials for neurodegenerave diseases. Though ROS accumulaon observed in glaucoma paents’ rena, nothing is known if Nrf2 acvaon could remove ROS and protect human RGC neurons as a potenal therapy for glaucoma. In this proposal we will use human stem cell derived RGC neurons and test if Nrf2 acvaon could serve as neuroprotectant under glaucomatous condion.2021 RESEARCH GRANTS

Forecasng Glaucoma Progression and the Need for Surgical Intervenon using Arcial IntelligencePrincipal Invesgator: Linda Zangwill, PhD Sally Baxter, MD, MSc (Co-Principal Invesgator) Mark Christopher, PhD (Co-Principal Invesgator) Viterbi Family Department of Ophthalmology Shiley Eye Instute, Hamilton Glaucoma Ctr. UC San DiegoPrimary open angle glaucoma is a leading cause of blindness in the United States and worldwide. However, there is no way to predict in advance which individuals are at greatest risk of progressing to vision loss in paents who are diagnosed and then medically treated for glaucoma. Such paents might then be considered for surgical intervenon to delay vision loss. There have been important innovaons in arcial intelligence (AI) applicaons in healthcare, in general, and parcularly in ophthalmology. Although considerable progress has been made in developing AI algorithms to detect glaucoma using imaging and visual eld data, few have integrated these results in one model. Even fewer have incorporated informaon from clinical examinaons and electronic medical records to support clinical decision-making. This study is designed to address this important unmet need. The overall objecve of this proposal, “Forecasng Glaucoma Progression and the Need for Surgical Intervenon using Arcial Intelligence”, is to use mulmodal AI and deep learning strategies to predict which glaucoma paents will need glaucoma surgery. We will leverage exisng data from diverse research datasets and real-world clinical glaucoma populaons for the development and tesng of the deep learning models. Data from clinical examinaons, electronic health record data, opcal coherence tomography imaging and visual eld tesng will be used as input for the development and tesng of the AI algorithms that can predict which paents will likely need glaucoma surgery. 2021 -2022 RESEARCH GRANT IN AI

Linda Zangwill, Ph.D, is Professor of Ophthalmology and co-Director of Clinical Research and Director of the Imaging Data Evaluaon and Analysis (IDEA) Center at the Hamilton Glaucoma Center. Dr. Zangwill received her M.S. at the Harvard School of Public Health and her Ph.D. from Ben-Gurion University of the Negev.Dr. Zangwill’s research focuses on improving our understanding of the complex relaonship between structural and funconal change over me in the aging and glaucoma eye, developing computaonal and stascal techniques to improve glaucomatous change detecon, and idenfying risk factors that can predict rapidly progressing glaucoma.As Director of the Imaging Data Evaluaon and Analysis (IDEA) Center, Dr. Zangwill has developed and implemented protocols for ulizing diagnosc imaging instruments in naonal and internaonal mutli-center clinical trials of glaucoma and ocular hypertension.The three UCSD Principal Invesgators, Linda Zangwill, PhD, Sally Baxter, MD, MSc and Mark Christopher, PhD are joined by invesgators Robert N. Weinreb MD (UCSD), Christopher Girkin MD, MPH and Massimo Fazio, PhD (University of Alabama, Birmingham), and Jerey Liebman MD (Columbia University) to complete this important work. This proposal will build upon the prior work conducted by this research team to develop AI algorithms that incorporate a variety of data types to improve forecasng of clinical outcomes for glaucoma paents2021 -2022 RESEARCH GRANT IN AI

Elasc Fibers and Exfoliaon GlaucomaPrincipal Invesgator: Rachel W. Kuchtey, MD, PhDVanderbilt Eye InstuteExfoliaon glaucoma (XFG) is one of the most common types of secondary glaucoma, which will lead to irreversible blindness if le without treatment. In order to eecvely treat this disease, precise understanding of its molecular mechanisms is needed. The breakthrough genec discoveries over the last decade have paved the pathways leading toward our goal. LOXL1, encoding lysyl oxidase-like 1 protein is the most signicant gene associated with XFG and the interacon between lysyl oxidase-like 1 and brillin-1 has been increasingly recognized as they are two essenal elements for proper elasc ber formaon and funcon. We propose to use our newly created mouse model supported by The Glaucoma Foundaon during the rst funding cycle to invesgate the roles of those two molecules in XFG. If successful, new treatments could be quickly tested in our model in the near future.“As a glaucoma clinician, I have deep appreciation on how the disease impacts a patient’s life and I will draw great satisfaction when we can get the disease under control one patient at a time. However, my decade and a half experience in the clinic also tells me we need a permanent x. It is clear to me that only through in-depth basic science research can we make the cure of glaucoma possible.” 2021 RESEARCH GRANTS

New Tools to Understand Intraocular Pressure Regulaon at the Level of Aqueous Veins and Sclera ComplexPrincipal Invesgator: Guan Xu, PhDUniversity of MichiganA great proporon of paents with glaucoma, especially those with exfoliaon glaucoma that progresses rapidly, require surgical intervenon to avoid blindness. However, the lack of knowledge of how aqueous drainage paths behave when pressure in the eye uctuates is a crical barrier to the accurate predicon of surgical outcomes. The goal of this proposed project is to ll this knowledge gap using an advanced imaging technology combined with an established mechanical analysis method. In our preliminary study, we have already shown that our approach can resolve the deformaon of aqueous drainage paths and the surrounding ssue in the eye in 3 dimensions, which has not been achieved by any exisng technology. During the funding period, we will further validate our approach by comparison to standard ssue measurement tools. Aer the validaon, we will analyze the deformaon of the aqueous drainage path and their surrounding sclera under well-controlled pressure in pig eyes and human donor eyes. These analyses will provide us with the knowledge needed for selecng appropriate surgical procedures for the most desirable paent outcomes. 2022 RESEARCH GRANTS

The Role of Le-Right Determinaon Factor 2 (LEFTY2) in Exfoliaon GlaucomaPrincipal Invesgator: Steven Bassne, PhDWashington University School of MedicineExfoliaon glaucoma is a potenally blinding condion aecng millions of people worldwide. Unfortunately, paents are oen unaware of this disease unl a signicant poron of their vision has been lost irretrievably. One of the goals of this project is to determine whether the levels of a protein called LEFTY2 can be used to diagnose the condion or predict which paents are likely to be aected most severely. The study will also examine which cells produce LEFTY2 and its eect on cells in the drainage pathway of the eye.2022 RESEARCH GRANTS

JOE AND MARILYN ROSEN GRANTMolecular Mechanisms of Reacve Astrocyte Neurotoxicity to Human Renal Ganglion CellsPrincipal Invesgator: Xiz Chamling, PhDJohns Hopkins University School of MedicineGlaucoma, the second leading cause of blindness, has no therapeuc approaches available except for lowering intraocular pressure. Drugs that can protect renal ganglion cells (RGCs), the neuronal cells whose death leads to vision loss in glaucoma, is a potenal therapeuc opon to prevent vision loss. However, developing such drugs has been dicult because the cause of RGC death in glaucoma is not fully understood. Several studies are now suggesng that another cell type, called astrocytes, that populate the brain and opc nerve (bundle of nerves that connect the eye to the brain), can release toxic factors when they are stressed and not funconing normally. Such stressed astrocytes are called reacve astrocytes and the factors secreted by them can kill the RGCs. In our lab, we have established methods to convert human stem cells to human RGCs and human reacve astrocytes in a dish. Using these cells, we plan to study how reacve astrocytes cause RGC death. By studying the cause of human RGCs death, we hope to idenfy targets for developing drugs to protect RGCs and prevent glaucoma-related vision loss.

A Novel Transcripon Factor for Neurodegeneraon Therapy in Glaucoma and Opc NeuropathyPrincipal Invesgator: Kun-Che Chang, PhDUniversity of PisburghGlaucoma is the second leading cause of blindness worldwide, esmated to aect ~80 million people in 2020. So far there is no permeant therapy for glaucoma. However, vision restoraon through gene delivery strategies could be potenal soluons for such a disease. In this proposal, we idenfy a novel therapeuc gene and will apply it to a glaucomatous animal model, which will not only provide us a deeper understanding of the molecular mechanism of this gene in neuroregeneraon therapy but also a foundaon of the translaonal experiment forpreclinic study.2022 RESEARCH GRANTS

Opc Nerve Head Perfusion in a Murine Model of Pathological MyopiaPrincipal Invesgator: Rachel Shujuan Chong, MBBS, MMed(Ophth), PhDSingapore Eye Research InstuteMyopia is an important risk factor for glaucoma – high myopia in parcular has been suggested to increase the risk of developing this sight-threatening disease by 3 to 7-fold. Elongaon of the eyeball that occurs in myopia oen results in deformaon of structures in the eye, including the opc nerve head where glaucoma damage occurs. It is possible that myopia-associated changes to the eye shape also aects the blood vessels that supply renal ganglion cells at the opc nerve head, although this has not been studied in great detail to date.We aim to invesgate how myopia can alter blood vessel structure and funcon around the opc nerve head using state-of-the-art methods of ocular imaging and ssue analysis in a mouse model of high myopia that demonstrates similar characteriscs as human myopia. Our study will enable deeper insight into the mechanisms that underlie myopia-associated glaucoma, which may help clinicians to idenfy paents who are most at risk of losing sight in future.2022 RESEARCH GRANTS

The Genec Landscape of Blinding Exfoliaon GlaucomaPrincipal Invesgator: Chiea Chuen Khor, MB, BS, DPhilSingapore Eye Research InstuteExfoliaon syndrome is a major cause of irreversible blindness throughout the world. This condion was found to be heritable and accordingly, genec variants showing signicant associaons with risk of exfoliaon syndrome have been discovered. However, comparavely lile has been done to invesgate the potenal role of human genes and propensity for progression towards blinding exfoliaon glaucoma. We rst asked whether CYP39A1, a gene where carriers of mutaons had a 2-fold increased risk of exfoliaon syndrome, would also be involved in exfoliaon glaucoma-related blindness. We observed that persons with exfoliaon syndrome carrying a loss-of-funcon CYP39A1 variant have >7-fold risk of blindness compared to persons with exfoliaon syndrome who did not carry any CYP39A1 variant. When only paents with exfoliaon glaucoma were considered, carriers of CYP39A1 G204E were observed to have 5.9-fold increased risk of blindness compared to non-carriers. Although we were encouraged that genec variants conferring such high odds of blindness actually exist, the associaon with CYP39A1 only explained between 10 to 20 percent of blindness due to exfoliaon glaucoma. We hypothesize that addional genes could be involved in this irreversible, debilitang process. To address this queson, we propose to perform long read sequencing mapping and search specically for structural variants that are strongly associated with blindness. Structural variants has yet to be systemacally studied, and will be accessible using long-read sequencing. Data from this proposal has the potenal to uncover genec markers that may be useful for idenfying individuals at high risk of exfoliaon syndrome related blindness.2022 RESEARCH GRANTS

Biochemical Characterizaon of LOXL1 and Eect of Variants Associated with Exfoliaon SyndromePrincipal Invesgator: Raquel L. Lieberman, PhDGeorgia Instute of TechnologyExfoliaon syndrome (XFS) is a leading risk factor for secondary glaucoma, a major cause of blindness worldwide. Genec changes in LOXL1 were discovered in connecon with XFS 15 years ago, yet how the LOXL1 gene product contributes to disease is sll unknown. In this proposal we will use state of the art biochemical techniques to characterize LOXL1 and elucidate the changes that occur with genec changes proposed either to cause or prevent XFS. In the long term, this study will result in new insights into how LOXL1 contributes to XFS/XFG, as well as new direcons for therapeucs.2022 RESEARCH GRANTS

Role of LOXL1 Variants in Elasc Fiber FormaonPrincipal Invesgator: Dieter P. Reinhardt, PhDMcGill UniversityExfoliaon syndrome (XFS) manifests as excessive deposits of abnormal elasc ber proteins in various organs, especially in the eye where it can lead to blindness. XFS is linked to the LOXL1 gene giving rise to the enzyme lysyl oxidase-like 1 (LOXL1) which is responsible to polymerize elasc bers. Small changes in LOXL1 termed “variants”, can either promote or protect from XFS. The objecve of this proposal is to analyze the consequences of specic LOXL1 variants with either protecve or risk proles on the funcon and development of elasc bers. We will analyze the structure and aggregaon of these LOXL1 variants, their interacon with elasc matrix proteins, and their contribuon to elasc ber formaon. We expect from the results of this project to beer understand how LOXL1 variants can either promote or reduce the risk of geng XFS. The project may even open new avenues for therapies for XFS.THE HARRIET AND STANLEY SLOANE GRANT FOR EXFOLIATION GLAUCOMA RESEARCH-2022

Niconamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical TrialPrincipal Invesgator: Simon John PhDColumbia University Irving Medical Center Glaucoma is the leading cause of irreversible blindness worldwide. Themost important test to detect progression is visual eld tesng. Visual eldtesng is the reference standard to measure visual funcon in glaucoma. Itis called called standard automated perimetry (SAP). However, this test isvery subjecve, oen unreliable, and variable. One of the main causes ofunreliable tests is the lack of aenveness or concentraon during the test.Previous studies have shown that listening to Mozart or taking vitamin B12 canimprove the reliability of this test. Recent studies have suggested that over-the-counter medicaons such as niconamide (vitamin B3) and pyruvate canalso improve the performance during this test. This can ulmately reduce costsdue to repeated tesng and increase doctor’s certainty when analyzing theresults of this test. This study seeks to test whether these over-the-counternutrional supplements have an impact on paents’ performance during visualeld tesng.BARRY FRIEDBERG AND CHARLOTTE MOSS GRANT

Vascular Genotype-Phenotype Associaon in Primary Open Angle GlaucomaPrincipal Invesgator:Lucy Q. Shen, MDHarvard Medical School Current treatment opons for glaucoma only lower eye pressure, but some paents connue to lose vision from damage to their opc nerves. This means there are other causes of glaucoma. We found that the small blood vessels supplying the opc nerve in the eye are decient in paents with glaucoma. This deciency matchesthe loss of blood vessels in the ngers of glaucoma paents, suggesng that glaucoma is a disease aecng the blood vessels not only in the eye but also in the body. The reason for the inadequacies of blood vessels may be genecs. A number of genes can increase the risk of glaucoma, and some of these genes also aectblood vessels. In this study, we will use the paent’s genec informaon to evaluate the genes aecng blood vessels and assess the connecon between genec risk and blood vessel deciency in the opc nerve and in the body of paents with glaucoma. We hope to show that some paents are losing vision from glaucoma dueto decient blood vessels, and this is caused by their genec make-up. This may lead to new ways to treat glaucoma by targeng the blood vessels and the genes that control them. 2023 RESEARCH GRANTS

Invesgang the Role of Impaired Mitochondrial Dynamics in Exfoliaon GlaucomaPrincipal Invesgators: Audrey Bernstein, PhDArunkumar Venkatesan, PhDSUNY Upstate Medical UniversityExfoliaon glaucoma (XFG) is a more severe form of open angle glaucoma and a blinding disease. The eye starts accumulang white aky brillar aggregates blocking uid exit from the eye. As XFG is a mulfactorial disease, evidence suggests that the pathogenesis of the disease is associated with genec variants, environmental factors, protein aggregaon, oxidave stress, and cellular dysfuncon. This proposal aims to study defects in mitochondrial funcon in XFG paentderived primary cells and the relaonship of mitochondrial dysfuncon to cellular senescence (aging cells). Mitochondria are essenal cellular organelles that play crical roles in cellular energy metabolism and are known to be responsible for oxidave stress-induced damage in age-dependent neurodegeneraons such as glaucoma. Hence, maintaining mitochondrial health is evolving as a fundamental part of prevenng aging diseases. This study will evaluate how mitochondrial funcon is impaired in XFG and examine therapeuc strategies to enhance mitochondrial funcon for the treatment of XFG.THE GLAUCOMA FOUNDATION / BRIGHTFOCUS FOUNDATION GRANT AWARD-2023

2023 RESEARCH GRANTSSearch for Funconal LOXL1 Risk Alleles with BiT-STARR-seqJohn H. Fingert, PhDCarver College of MedicineUniversity of IowaExfoliaon glaucoma is a common cause of vision loss and disability that has a strong genec basis. One gene, lysyl oxidase like 1 (LOXL1), has an outsized inuence on risk for exfoliaon glaucoma, with an odds rao as high as 20. However, the specic genec variants in or near the LOXL1 gene that confer this risk for exfoliaon glaucoma remain unknown. The goal of our proposal is to use cung edge technology (BiT-STARR-seq) to test dozens of LOXL1 genec variants in parallel to rapidly determine which are the source of risk for exfoliaon glaucoma. These experiments and others will reveal the causes of exfoliaon glaucoma at the most basic molecular level and provide the informaon needed to build new, targeted, more eecve therapies to prevent vision loss.

2023 RESEARCH GRANTSRe-Purposing an “Old” Drug for a New Indicaon: Elucidang the Peripheral and Central Eects of Glucagon-Like Pepde 1 Receptor Agonists to Treat GlaucomaQi N. Cui, MD, PhDPerelman School of MedicineUniversity of PennsylvaniaGLP-1R agonists are a popular class of therapy for type 2 diabetes mellitus and weight loss. These drugs have demonstrated early promise as a novel treatment for glaucoma that does not rely on lowering intraocular pressure. This study, building upon previous ndings from our lab, will delineate the ocular, circulang, and central eects of GLP-1R agonists, and to test the ecacy of dierent formulaons of an FDA-approved GLP-1R agonist, Exendin-4, for treang glaucoma. This proposal will reveal protecve pathways behind not only glaucoma but other neurodegenerave processes and seeks to posively impact human eye health by revealing a novel therapy for a blinding disease.

2023 RESEARCH GRANTSUsing Arcial Intelligence to Reveal Blood Pressure’s Role in Glaucoma ProgressionAlon Harris, MS, PhD, FARVOIcahn School of MedicineOpen-angle glaucoma is a leading cause of irreversible blindness historically associated with elevated eye pressure. However, many paents develop glaucoma and experience its connued disease progression despite low or medically reduced pressures. The signicant connued disease burden demonstrates the high importance of nding new, non-invasive, and highly accessible diagnosc targets. High and low blood pressure as well as impaired blood ow and oxygenaon in eye ssues have also been linked to glaucoma. Using blood pressure to help improve diagnosis and paent care, however, has been dicult due to the complexity of unraveling and quanfying the impact of blood pressure on the eye’s circulaon and disease progression. We solve these challenges by combining validated cung-edge arcial intelligence techniques with novel data from early-stage open-angle glaucoma paents followed over me. Already, we have observed early-stage glaucoma paents to have specic vascular insult surrounding the eye’s nerve cells before experiencing any vision loss. The proposed research is highly relevant to public health because blood pressure is easy to measure, highly accessible, and when properly described with new arcial intelligence techniques will be able to clarify the role of blood pressure in glaucoma disease and promote improved methods to preserve vision worldwide.

72024 RESEARCH GRANTSWhile elevated intraocular pressure is a strong risk factor for glaucoma other, pressure independent, disease mechanisms clearly contribute to vision loss in a large majority of paents. Our previous ndings, as well as those presented by other invesgators, have demonstrated that autoimmune reacons can develop during the disease resulng in slow but chronic vision loss. However, it is currently not clear how these immune reacons to become established in some paents. The immunoproteasome is a mul-enzyme complex that is crucial for the iniaon of immune responses. We propose to invesgate the role of the immunoproteasome in glaucoma using a mouse model of the disease. Highly specic inhibitors of this complex exist, and these have been shown to reduce damage in other neurodegenerave diseases. Consequently, demonstraon that acvaon of the immunoproteasome worsens glaucoma would provide strong support for the development of novel medical treatments aimed at preserving vision in glaucoma paents.Principal Invesgator, Markus H. Kuehn, PhD The University of IowaRole of the Immunoproteasome in Glaucoma Neuroinammaon

8 9Advanced In Vitro Model for Pseudoexfoliaon Syndrome and GlaucomaPseudoexfoliaon (PEX) syndrome is esmated to aect between 10 and 20% of people over the age of 60 and is frequently associated with a severe form of glaucoma that may account for over 25% of all open-angle glaucoma cases worldwide. Glaucoma in PEX paents is believed to result from accumulaon of an abnormal brillar matrix product (PEX material) in intra- and extraocular ssues. Currently there is limited informaon about the mechanisms leading to the producon of such material and there is no specic treatment to prevent its accumulaon in the eye. A major limitaon to develop specic therapies is the lack of experimental models, which are used to analyze disease mechanisms and to idenfy specic treatments to inhibit the producon of PEX material.Therefore, we have been invesgang the potenal of using cells from small iris ssue specimens rounely obtained during glaucoma surgery in PEX glaucoma paents to generate a cell culture model for the disease. Our preliminary results show that it is possible to replicate the formaon of an abundant extracellular matrix, which also contains the typical brillar PEX material.The objecve of the current applicaon is to use this cell culture model to evaluate the eects of various PEX-associated stress condions and metabolic factors on matrix producon in order to idenfy novel therapeuc targets. In addion, immortalized cell lines will be generated to provide consistency in experimental approaches and open an opportunity to use this model by invesgators in the eld. Availability of such model should open new avenues to understand the disease and develop specic treatments.Principal Invesgator, Ursula Schlötzer-Schrehardt, PhD University of Erlangen-Nürnberg2024 RESEARCH GRANTS

9Targeng Primary Cilia Signaling for Glaucomatous Opc NeuropathyGlaucoma damages the opc nerve, leading to a slow and permanent loss of eyesight. This occurs because the cells in the rena and opc nerve deteriorate over me. To preserve and potenally restore vision, sciensts are exploring the role of cilia in promong the growth of nerve cells and improving how the rena responds to light. Using a new method, researchers are studying live mice to understand how changes in eye pressure aect the cilia signaling of nerve cells in the rena. They hope this will shed light on how cilia could help protect the opc nerve from damage.Principal Invesgator, Yang Sun, MD, PhD Stanford University2024 RESEARCH GRANTS

10 11THE JOE AND MARILYN ROSEN & RAJEN SAVJANI GRANT AWARDSPrincipal Invesgator, Thomas V , MD, PhD Johns Hopkins University School of MedicineOur laboratory has recently made groundbreaking progress in the transplantaon of human stem cell derived renal ganglion cells (RGCs), an approach that holds promise for therapeuc restoraon of vision in paents suering from opc neuropathies including glaucoma. Rigorous prior research in our laboratory and others has idened a number of molecular pathways that, if appropriately manipulated, strongly increase the resilience of RGCs and have been idened as candidate “neuroprotecve” targets. These include the genes PTEN, SOCS3, DLK, BAX, and NMNAT2. To replace a paent’s RGCs with new neurons that are especially resilient and regenerave, and likely to survive for the life of the paent, we propose to genecally engineer the RGCs that will be used for transplantaon. Moreover, to accelerate and streamline the developmental pipeline, we propose to integrate longitudinal in vivo imaging into our workow. Currently, our experiments are conducted by performing histology on ssues following humane euthanasia of experimental animals. Histology requires numerous me-consuming steps to prepare the ssue for imaging, and then requires laborious microscopy. However, new technologies have been developed that enable invesgators to capture uorescent microscopy images of the rena in living mice, rats, and nonhuman primates by taking a picture through the cornea – akin to when human paents have photographs of their renas or opc nerves taken. By combining genec engineering of human RGCs with longitudinal in vivo imaging of RGC transplants, we will be able to quickly and eciently screen novel cell lines to determine those that best achieve long term survival and integraon into the rena.Longitudinal Evaluaon of Genecally Engineered RGC Transplants in Living Models

11Principal Invesgator, Adriana Di Polo, PhD University of MontrealRenal ganglion cells (RGC), the neurons that die in glaucoma, are metabolically acve and require a precise regulaon of blood supply to meet their high oxygen and nutrient demand. The vascular theory of glaucoma proposes that insucient blood ow contributes to RGC neurodegeneraon. Glaucoma paents suer from vascular decits including decreased blood ow in the rena and opc nerve, reduced vessel caliber, and capillary defects. Notably, vascular autoregulaon and icker-induced neurovascular coupling, a key process that matches blood ow to the metabolic demand of acve neurons, are severely compromised in this disease. However, the cellular mechanisms underlying vascular dysfuncon in glaucoma and their impact on neuronal damage are currently unknown. Pericytes, the ensheathing cells that wrap around capillary walls, have emerged as key regulators of microcirculatory blood ow and neurovascular coupling. Pericytes are centrally posioned within the neurovascular unit, contain contracle proteins, and respond rapidly to neuronal smulaon. The renal microvasculature is rich in pericytes, with >90% pericyte coverage in human renal capillaries. We recently reported that inter-pericyte tunneling nanotubes (IP-TNTs), ne tubular processes that connect renal pericytes on distal capillary systems, are essenal for neurovascular coupling in the rena. These ndings were published in the impacul journal Nature (2020) and were lauded as crically important by the scienc community at large. Despite this, the role of pericytes and IP-TNTs in vascular dysregulaon in glaucoma has not been invesgated. To ll this knowledge gap, we recently developed a novel two-photon laser scanning microscopy Undercovering the Potenal of Pericytes as Therapeuc Targets for GlaucomaKUMAR MAHADEVA GRANT AWARD

12 13THE KEN AND LINDA MORTENSONGRANT AWARDThis one-of-its-kind research project is designed to correlate genec predisposion to glaucoma with actual ophthalmic outcomes. We have assigned everyone in two Biobanks one at Mount Sinai and another at Mass General Brigham - a glaucoma genec predisposion score. We invite subjects with the highest and lowest genec risk scores for a 3-hour exam that includes visual eld tesng, imaging of the opc nerve with the latest technologies, and various measurements of eye size and shape. We also take extensive histories regarding diet, dental status, and female reproducve health because these factors may modify the relaon between genec predisposion to glaucoma and the actual development of the disease.When the NIH reduced funding for this project, we were faced with the possibility of reducing the number of people invited to parcipate. This grant allows us to idenfy associaons between genec risk and the development of glaucoma and to recognize crical dietary and lifestyle factors that might impact the genec risk of developing glaucoma. Overall, we plan to recruit 400 subjects with a low genec predisposion to glaucoma and another 400 with the highest propensity to glaucoma.The study has a high chance of moving the eld of glaucoma forward. Genec proling could play a major role in eecvely idenfying glaucoma early, an important priority for The Glaucoma Foundaon.Understanding the Clinical Impact of Cumulave Genec Risk to GlaucomaPrincipal Invesgator, Louis R. Pasquale, MD, FARVO Mount Sinai Health System

13Advanced 3D Spheroid Model for Pseudoexfoliaon Syndrome and GlaucomaPseudoexfoliaon (PEX) syndrome is esmated to aect between 10% and 20% of people over the age of 60 and is frequently associated with a severe form of glaucoma that may account for over 25% of all open-angle glaucoma cases worldwide. Glaucoma in PEX paents is believed to result from accumulaon of an abnormal brillar matrix product (PEX material) in intraocular ssues. Currently there is limited informaon about the mechanisms leading to the producon of such material and there is no specic treatment to prevent its accumulaon in the eye. A major limitaon to develop specic therapies has been the lack of experimental models, which are used to analyze disease mechanisms and to idenfy specic treatments to inhibit the producon of PEX material.Principal Invesgator, Ursula Schlötzer-Schrehardt, PhD University of Erlangen-Nürnberg2024 RESEARCH GRANTS

14 15Childhood glaucomas are a leading cause of pediatric blindness worldwide aecng the opc nerve, the cable that sends visual signals to the brain. While there have been advances in genec tesng for glaucoma, most of the cases do not have a clear idened cause. The Childhood Glaucoma Genecs Group (CG3) is a mul-instuonal collaborave eort formed to improve our understanding of the genecs of childhood glaucoma. In this proposal, we leverage data from over 150 families whose DNA has undergone whole genome sequencing. Our goal is to dene genes that are associated with childhood glaucoma and to idenfy and validate new types of genec variants in exisng genes, such as variants that impact the expression of a gene. We have idened one such new gene, which had previously been implicated in a neurodevelopmental disorder and we will use genec signatures for this gene to help validate its role in glaucoma. Our studies will have direct implicaons for our paents and families by assessing glaucoma risk. Strafying paents based on genec and mechanisc cause will also allow us to beer select appropriate therapies for paents. Findings from these rare disorders may have therapy implicaons for more common forms Dening Novel Genes and Syndromic Associaons in Childhood GlaucomaPrincipal Invesgator, Lev Prasov, MD, PhDUniversity of Michigan2024 RESEARCH GRANTS

15Mechanotransducon Pathways for Neuroprotecon in GlaucomaGlaucoma is a progressive, blinding disease for which intraocular pressure is the most signicant risk factor, and yet, the mechanisms of how the eye senses pressure remain largely unknown. Mechanosensive ion channels are pressure sensors that may be involved in glaucoma pathology. This project will invesgate the role of a mechanosensive ion channel in glaucoma, and how modulang the acvity of this channel may protect renal ganglion cells from dying in glaucoma. It will also explore how signaling pathways downstream of mechanotransducon may lead to neuroprotecon. These studies will provide fundamental insights into mechanotransducon pathways in renal ganglion cells and inform the development of new neuroprotecve therapies for glaucoma.Principal Invesgator, Wendy Liu MD, PhDStanford University Spencer Center for Vision Research2024 RESEARCH GRANTS

16 17Resilience Therapies for Neuroprotecon and RegeneraonGlaucoma is a neurodegenerave disease that leads to the death of renal ganglion cells (RGCs) and remains a major cause of blindness, aecng more than 80 million people worldwide. It commonly involves elevated intraocular pressure (IOP), which stresses and damages RGCs. The molecular processes linking high IOP to RGC injury are only partly understood.We are determining how elevated IOP damages renal neurons and developing new resilience-centered treatments that target IOP, renal neurons, or both. Our approach is to strengthen cellular defenses by restoring metabolism and enhancing protecve processes. We are parcularly focused on using natural molecules that act as resilience factors. These molecules improve the ability of ocular ssues to resist stress and, when applied early enough, may even delay or prevent disease development.Our studies in mice have idened alteraons in NAD metabolism, along with disrupted glucose and pyruvate pathways, in glaucoma. Supplementaon with vitamin B3 (niconamide), a precursor of NAD, provided strong protecon against disease. Pyruvate also oered protecon, and the combinaon of vitamin B3 and pyruvate was more eecve than either alone. These results laid the groundwork for clinical trials now underway, with promising early outcomes.The current project focuses on the eye’s drainage ssues, which regulate IOP. By applying resilience treatments, we aim to reduce IOP elevaon and limit glaucomatous damage. As changes in drainage ssues occur earlier than RGC degeneraon, they provide an opportunity to opmize dosing and rene strategies before iniang longer-term neuroprotecon and regeneraon studies. These experiments will also enable more rapid dose opmizaon prior to extended tests. Importantly, resilience treatments may provide a dual benet by both lowering IOP and directly protecng renal neurons.This invesgaon is into the protecon of the ocular drainage ssues and lessening IOP elevaon to harness resultant neuroprotecve eects, which can also benet regeneraon eorts. Dr. John expects to have data on the drainage ssues/IOP earlier along the path to tesng neuroprotecon, and will use these measures to inially opmize dosing for the longer-term neuroprotecon experiments.Principal Invesgator, Simon John, PhDColumbia UniversityTHE RAJEN SAVJANI GRANT AWARD

17Resilience Therapies for Neuroprotecon and RegeneraonGlaucoma is the world’s most common neurodegenerave disease and the leading cause of irreversible blindness, projected to aect 111.8 million people by 2040. Convenonal treatments that lower intraocular pressure (IOP) slow the disease, but many paents connue to lose vision despite successful IOP lowering. There is a pressing need for new therapies that directly protect, and even restore, renal ganglion cells, the neurons that die in glaucoma.Our research revealed that metabolic and mitochondrial dysfuncon appear in these cells well before detectable opc nerve damage. Niconamide is a parcularly promising candidate to protect these cells: it improves mitochondrial health and protects neurons in both glaucoma and other condions. Pyruvate, too, plays a key role; its depleon in the rena is linked to abnormal glucose metabolism in glaucoma models. Our laboratory studies show that combining niconamide and pyruvate is signicantly more eecve than either alone in prevenng glaucomatous degeneraon.Based on these ndings and inial short term (few months) clinical trials, we are conducng a 20-month, mulcenter, placebo-controlled trial of niconamide plus pyruvate supplementaon. This is one of the rst long-term tests of metabolic resilience therapy in glaucoma, with the potenal to shi the standard of care toward neuroprotecon.Principal Invesgator, Simon John, PhDColumbia UniversityBARRY FRIEDBERG & CHARLOTTE MOSS GRANT AWARD Niconamide and Pyruvate for Primary Open Angle Glaucoma: A Mulcenter Randomized Clinical Study

18 19Metabolic and MolecularStudies of GlaucomaOur mission is to unlock a new molecular understanding of glaucoma so we can stop vision loss. We are working to create safe, metabolism-supporng therapies and nutrional supplements that strengthen the eye from within.Current glaucoma treatments, while helpful, leave too many paents vulnerable to irreversible vision loss. Our resilience-focused strategy aims to boost the eye’s own defenses by (1) restoring balance to key energy and metabolic pathways, (2) reducing damaging oxidave stress, and (3) reinforcing the body’s natural repair and maintenance systems. We have already shown that administering natural resilience factors such as niconamide (NAM) and pyruvate (PYR) enhances the eye’s capacity to withstand glaucoma-related stress. Using these molecules together is central to our approach, and they are currently being tested in an ongoing, placebo-controlled clinical trial.This project is uncovering the molecular changes triggered by NAM and PYR treatment—and why some individuals respond beer than others. At clinic visits during the trial, blood samples are collected and carefully processed into mulple stable forms (plasma, cell lysates, cryopreserved cells). These samples provide a rich resource for advanced analyses—transcriptomics, metabolomics, and mitochondrial funcon. By storing samples to batch high-costs analyses, we maximize the impact of each dollar. The complementary molecular datasets that we are building will clarify protecve mechanisms, idenfy biomarkers of response, guide therapeuc improvements and enable personalized therapy.Principal Invesgator, Simon John, PhDColumbia UniversityBARRY FRIEDBERG & CHARLOTTE MOSS GRANT AWARD

19Dual Targeng of Neuroprotecon and Neuroregeneraon in GlaucomaGlaucoma is the most common cause of irreversible blindness. Globally, the disease aects 80 million people. Glaucoma is costly both for society and the individual and aects the quality of life for the suerer. Paents with glaucoma suer from a gradual breakdown of the opc nerve, usually caused by high eye pressure. The job of the opc nerve is to transmit visual impressions from the rena of the eye to the brain, but once the opc nerve is damaged, it cannot be repaired. There are methods to lower the eye pressure in glaucoma paents, but there is no clinical method to treat a damaged opc nerve. In many paents the opc nerve ruptures despite lowering the pressure and because of this there is a great need to nd methods that treat both the rena and the opc nerve.I have recently discovered that niconamide (a variant of vitamin B3) can protect the opc nerve by aecng these degrading processes. Niconamide is inexpensive, eecve, and has few side eects, making it an ideal candidate for the treatment of glaucoma paents. I plan to further develop these ndings to develop new methods to protect the neurons. I focus my research on the neurodegenerave processes and to nd treatments in animal models that can be transferred to paents in clinical pracce. My research group priorizes well-documented substances and gene therapy that can therefore be used directly in clinical pracce. In this part of the project, we will collaborate with leading glaucoma specialists at St. Erik’s Eye Hospital to invesgate potenal biomarkers as well as apply for and conduct clinical studies based on the research results.The opc nerve connects the rena of the eye to the brain, which in turn processes these complex visual signals. When the opc nerve is damaged, the vision loss is irreversible. Our collaborave team (Pete Williams, Karolinska Instutet and Richard Eva, King’s College London) will now address the following: can we simultaneously target neuroprotecon and axon regeneraon to develop a comprehensive intraocular therapy for glaucoma and opc neuropathy? We will use our knowledge gained from the niconamide pre-clinical and clinical work as well as our experse in regenerave mechanisms to achieve this. Accomplishing these goals will lead to a new therapeuc strategy for glaucoma that has relevance for glaucoma paents at mulple stages of the disease.Principal Invesgator, Pete A. Williams, PhDDocent, St Erik Eye HospitalKarolinska Instutet2024 RESEARCH GRANTSMetabolic and MolecularStudies of Glaucoma

20 21Glaucoma is a leading cause of irreversible blindness worldwide. The obstrucon of uid oulow from inside of the eye leads to elevated pressure in the eye. Currently glaucoma surgeons do not have sucient understanding of the mechanism of the uid oulow in the eye. Therefore, they have diculty in selecng the appropriate surgeries for glaucoma paents, especially those with exfoliaon. This study establishes an experiment plaorm, including a clinically relevant model with donor human eyes and an advanced imaging system to observe the uid oulow, to ll this long exisng gap in knowledge. Using this plaorm, we will aempt to test our hypothesis that paents with s scleral ssue are likely to have high pressure in their eyes.Understanding the Contribuon of the Distal Aqueous Oulow to Intraocular Pressure RegulaonPrincipal Invesgator, Guan Xu, PhDUniversity of MichiganGlaucomatous opc neuropathy is a leading cause of blindness aecng millions of Americans. All FDA-approved treatments lower eye pressure, a major glaucoma risk factor, but do not address other important aspects of the disease. More eecve therapies are needed to prevent neuronal loss. Biomechanical changes at the opc nerve head are central to disease severity and progression. The goal of this project is to develop treatment strategies in a laboratory model that modulate the biomechanics of the eye. If successful, this could suggest new treatment strategies for glaucoma and other opc neuropathies.Targeted Delivery of Enzymes to Modulate Opc Nerve Head BiomechanicsPrincipal Invesgator, Bryce Chiang, MD, PhDWilmer Eye Instute at Johns Hopkins Hospital2024 RESEARCH GRANTS

21Ecacy of Insulin Eye Drops in the Treatment of Open Angle Glaucoma: A Phase II Clinical TrialA crucial element in the pathophysiology of glaucoma is the death of renal ganglion cells (RGCs), specialized neurons that transmit visual informaon from the rena to the brain via their axons in the opc nerve2. Clinically, such changes result in progressive visual eld loss and may even lead to total blindness. Currently, intraocular pressure (IOP) reducon remains the sole therapy for glaucoma through various opons 3. However, many paents connue to lose vision despite adequate IOP control4, highlighng the need for new strategies to preserve RGCs survival and to promote their regeneraon.Insulin is a pepde hormone secreted by the pancreas that can cross the blood-brain-barrier and acvate insulin receptors expressed by neurons and glia. Abnormal insulin signaling, even in the absence of diabetes, is associated with neurodegenerave diseases characterized by dendric damages, such as Alzheimer’s disease, Parkinson’s disease, and glaucoma. In a landmark study using a mouse model of opc nerve axotomy, members of our team demonstrated that insulin, administered either systemically or topically as eye drops, was eecve in promong robust dendric regeneraon and RGC survival. More recently, we demonstrated that daily human recombinant insulin eye drops smulate RGC dendrite and synapse regeneraon during ocular hypertension damage (OHT). Furthermore, we showed that insulin enhances neuronal survival and rena-brain connecvity leading to improved optomotor reex-elicited behavior. Insulin inslled as eye drops has been shown to readily reach the rena without causing hypoglycemia, and clinical studies of insulin eyedrops in healthy volunteers or diabec paents showed that this approach is well tolerated. Taken together, these results provide a compelling example of RGC regeneraon and funconal recovery by insulin administraon oering the possibility of developing this strategy to treat glaucoma paents.Principal Invesgator, Jerey L. Goldberg MD, PhD Stanford University THE RAJEN SAVJANI GRANT AWARD

20 21

Advanced 3D Spheroid Model for Pseudoexfoliaon Syndrome and Glaucoma Ursula Schlötzer-Schrehardt, PhD University of Erlangen-Nürnberg Pseudoexfoliaon (PEX) syndrome is esmated to aect between 10% and 20% of people over the age of 60 and is frequently associated with a severe form of glaucoma that may account for over 25% of all open-angle glaucoma cases worldwide. Glaucoma in PEX paents is believed to result from accumulaon of an abnormal brillar matrix product (PEX material) in intraocular ssues. Currently there is limited informaon about the mechanisms leading to the producon of such material and there is no specic treatment to prevent its accumulaon in the eye. A major limitaon to develop specic therapies has been the lack of experimental models, which are used to analyze disease mechanisms and to idenfy specic treatments to inhibit the producon of PEX material. In the previous funding period, we developed an in vitro model using small iris ssue specimens rounely obtained during glaucoma surgery in PEX glaucoma paents. Our ndings demonstrate that this model replicates the formaon of an abundant extracellular matrix, which also contains the typical brillar PEX material. The matrix formaon could be modulated by various PEX-associated stress condions and metabolic factors conrming suitability of the model to invesgate PEX-relevant pathologic processes and potenal intervenons. In addion, immortalized cell lines have been generated to provide consistency in experimental approaches for interested invesgators in the eld. The objecve of the current applicaon is to expand the use of this new culture model to explore how TGF-ß1, a key driver of PEX-associated brosis, aects gene acvity and matrix deposion on a broader scale using transcriptomics and proteomics techniques. We also plan to create a chronic 3D stress model to study how PEX-related stress factors inuence the formaon of PEX material and whether an-broc agents can alter or reduce this process. These studies will further enhance our understanding of PEX as a disorder of the extracellular matrix and may provide crical insights for idenfying novel therapeuc targets. 2025 RESEARCH GRANTS

2025 RESEARCH GRANTSVascular Genotype-Phenotype Associaon in Primary Open Angle Glaucoma Lucy Shen, MD Harvard Medical School Current treatment opons for glaucoma only lower eye pressure, but some paents connue to lose vision from damage to their opc nerves. This means there are other causes of glaucoma. We found that the small blood vessels supplying the opc nerve in the eye are decient in glaucoma. This deciency matches the loss of small blood vessels in the ngers of glaucoma paents, suggesng that glaucoma is a disease aecng small blood vessels in the eye and in the body. The reason for the inadequacies of blood vessels may be genecs. Several genes can increase the risk of glaucoma, and some of them also aect blood vessels. In the connuaon of this study, we will use the paent’s genec informaon to evaluate the genes aecng blood vessels and assess the connecon between genec risk and blood vessel deciency in the opc nerve and in the ngers of paents with glaucoma. We hope to show that some paents are losing vision from glaucoma due to decient blood vessels, and this is caused by their genec make-up. This may lead to new ways to treat glaucoma by targeng the blood vessels and the genes that control them.

The Role of Periosn in Early-Onset Glaucomas Revathi Balasubramanian, PhD Columbia University The trabecular meshwork (TM) and the Schlemm’s canal (SC) are drainage ssues in the eye. Their funcon is crical for the maintenance of normal eye pressure. Paents with early-onset forms of glaucoma typically have mal-formed TM and SC. It is therefore crical to understand the development of TM and SC under normal condions and to create mouse models to study early-onset glaucoma and design therapies. Previously, a gene called Periosn was discovered to be important in TM development. In this proposal we aim to thoroughly study the importance of Periosn in TM development and hence early-onset glaucomas. Successful compleon of this project will yield a useful mouse model for the eld to study early-onset glaucomas. Paravascular Clearance as a Potenal New Treatment for Normal Tension GlaucomaLuis Alarcon-Marnez, PhD University of Melbourne/Centre for Eye Research Australia This project will focus on glaucoma, the leading cause of irreversible blindness worldwide. Here, we will study how the rena – a photosensive layer located at the back of our eyes, removes waste products, whose excess may lead to sight loss. We will use state-of-the art methods only available in our laboratory at the Centre for Eye Research Australia/University of Melbourne. Our results will improve the treatment and prevenon of glaucoma in people suering from all types of glaucoma, including people with normal intraocular pressure. 2025 RESEARCH GRANTS

2025 RESEARCH GRANTSEstablishing Diurnal Curves in Mitochondrial Acvity, Oxygen Metabolism, Blood Flow and Waste Clearance in Persons with and without Primary Open Angle Glaucoma Keren Wood Shalem, MD & Alon Harris, MS, PhD, FARVO Icahn School of Medicine at Mount Sinai Glaucoma remains a leading cause of blindness worldwide, despite therapeuc reducon of eye pressure. Other factors associated with the disease include the eye’s metabolic funcons, blood ow, oxygenaon and waste clearance. While researchers aim to target non eye pressure risk factors including metabolic distress in glaucoma, lile is known about the uctuaons in these biomarkers throughout the day. This project is designed to establish how metabolic processes, blood ow, oxygenaon and waste clearance in the eye change throughout the day in persons with and without glaucoma. We will further apply arcial intelligence mathemacal modelling to reveal interconnecvity of these factors and their relaonship to glaucomatous disease and its progression. The study will evaluate 36 parcipants: 18 with primary open angle glaucoma and 18 healthy controls. Using advanced non-invasive imaging tools, we will capture comprehensive data on eye cellular metabolism, blood ow, oxygenaon and waste clearance in persons with and without glaucoma at seven dierent mes throughout the day. This cung-edge study will both provide signicant clinical discoveries and establish the foundaon for larger trials aiming to target metabolic disturbances in glaucoma. Ulmately results will help individualize glaucoma treatments and may inform on many other neurodegenerave diseases.

2025 RESEARCH GRANTSAutophagy Acvaon in Renal Ganglion Cells Restores Axonal Transport and Migates Glaucomatous Neurodegeneraon Gulab Zode, PhD The Regents of the University of California, Irvine Primary open-angle glaucoma (POAG) is a complex eye disorder characterized by increased intraocular pressure (IOP) due to defects in the eye’s natural drainage system. This elevated pressure can harm the light-sensive nerve cells in the rena, called renal ganglion cells (RGCs), potenally leading to irreversible vision loss. Current therapeuc approaches primarily focus on reducing eye pressure through medicaons or surgery. However, many paents experience vision loss even with treatment. This points towards other factors, beyond eye pressure, contribung to nerve damage in glaucoma. Renal ganglion cells are the bridge between the eye and the brain. They transmit visual informaon from the eye to the brain via long axons; ecient transport across them is the key to sending visual informaon to the brain. Failure of a transport system RGCs occurs in POAG, which leads to harmful materials building up, causing nerve cell damage. In this proposal, we will explore whether promong autophagy restores transport failure in a mouse model of glaucoma.

Louis Pasquale, MD, FARVO, ChairSite Chair, Department of Ophthalmology, Mount Sinai Hospital Vice Chair, Translational Ophthalmology ResearchMichael Anderson, PhDProfessor, Department of Molecular Physiology and Biophysics Carver College of Medicine Iowa Glaucoma Center, Institute for Vision ResearchAudrey Bernstein, PhDProfessor, Center for Vision ResearchDepartment of OphthalmologySUNY Upstate Medical UniversityTerete Borrás, PhD Professor, Department of Ophthalmology Gene Therapy CenterUniversity of North Carolina School of Medicine Jonathan G. Crowston, BSc, MBBS, PhD, FRCOphth, FRANZCOProfessor of Ophthalmology, Centre for Vision Research Duke-NUSSingapore Eye Research InstituteJohn Danias, MD, PhDProfessor and Interim Chair, Department of OphthalmologyState University of New York - DownstateC. Gustavo De Moraes, MD, PhD, MPHAssociate Professor of Ophthalmology Columbia University Irving Medical CenterChief Medical Ocer, Ora Clinical, Inc.Adriana Di Polo, PhDProfessor in Neuroscience and OphthalmologyCanada Research Chair in Glaucoma and Age-Related NeurodegenerationUniversity of MontrealJohn H. Fingert, MD, PhD, FARVOHadley-Carver Chair in GlaucomaProfessor and Director of the Glaucoma ServiceDepartment of Ophthalmology and Visual SciencesCarver College of Medicine, University of IowaDirector, Glaucoma Research Center, Institute for Vision ResearchScientific Advisory BoardT MGiovanna Guidoboni, PhDDean, Maine College of Engineering and ComputingProfessor, Electrical and Computer Engineering, University of MaineAdjunct Professor, OphthalmologyIcahn School of Medicine at Mount SinaiElected Member, European Academy of Sciences and Arts Jerey L. Goldberg, MD, PhDProfessor and Chair, Department of OphthalmologyByers Eye Institute at Stanford University Neeru Gupta, MD, PhD, MBA, FRCSC, DABOProfessor and Dorothy Pitts ChairChief of Glaucoma, University of TorontoDepartments of Ophthalmology & Vision SciencesLaboratory Medicine and PathobiologyFaculty of MedicineProfessor, Dalla Lana School of Public Health University of TorontoDirector, Roy Foss and Family Glaucoma LaboratoryKeenan Research Centre for Biomedical ScienceLi Ka Shing Knowledge Institute, St. Michael’s HospitalAlon Harris, MS, PhD, FARVO Professor of OphthalmologyProfessor of Artificial Intelligence & Human Health Vice Chair of International Research and Academic AairsDirector, Ophthalmic Vascular Diagnostic & Research Pgm.Co-Director of the Center for Ophthalmic ArtificialIntelligence & Human Health, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai Thomas V. Johnson III, MD, PhDThe Shelley & Allan Holt Assistant Professor of OphthalmologyAssistant Professor of Cellular and Molecular MedicineWilmer Eye Institute, Johns Hopkins UniversityJae Hee Kang, ScDAssociate Professor of MedicineBringham and Women’s HospitalAnthony Khawaja MA(Cantab) PhD FRCOphthProfessor of Ophthalmology UCL Institute of OphthalmologyHonorary Consultant Ophthalmic Surgeon Moorfields Eye Hospital Richard K. Lee, MD, PhDWalter G. Ross Distinguished Chair in Ophthalmic ResearchAssociate Professor of Ophthalmology, Cell Biology, and Neuroscience Graduate ProgramBascom Palmer Eye InstituteUniversity of Miami Miller School of Medicine

Jerey M. Liebmann, MDShirlee and Bernard Brown Professor of OphthalmologyVice Chair, Department of Ophthalmology Director, Glaucoma ServiceEdward S. Harkness Eye Institute Columbia University Irving Medical Center Yutao Liu, MD, PhDAssociate ProfessorCellular Biology & Anatomy Graduate StudiesAugusta UniversityStuart MacGregor, PhDSenior Group Leader, Statistical Genetics LabQIMR Berghofer Medical Research InstituteAustraliaFelipe Medeiros, MD, PhDProfessor of OphthalmologyVice-Chair of Translational ResearchBascom Palmer Eye Institute, University of Miami School of MedicineColm O’Brien, FRCS, MDProfessor of OphthalmologyMater Misericordiae University HospitalDublin, IrelandDieter Reinhardt, PhDDistinguished James McGill ProfessorFaculty of Medicine and Health Sciences & Faculty of DentistryMcGill UniversityUrsula Schlötzer-Schrehardt, PhDProfessor, Department of OphthalmologyUniversity of Erlangen–NürnbergAyellet V. Segrè, PhDAssistant Professor of OphthalmologyHarvard Medical SchoolDirector, Biostatistics and Bioinformatics CoreOcular Genomics Institute, Massachusetts Eye and EarAssociate Member, Center for Genomics Medicine, MGHAssociate Member, Broad Institute of Harvard and MITJoel S. Schuman, MD, FACSElaine Langone Professor & Vice Chair for ResearchDepartment of OphthalmologyProfessor of Biomedical EngineeringElectrical & Computer Engineering, Neuroscience & Physiology, and Neural ScienceNYU Langone HealthW. Daniel Stamer, PhDJoseph A. C. Wadsworth Professor of OphthalmologyProfessor of Biomedical EngineeringDuke UniversityJoshua D. Stein, MD, MSAssociate ProfessorUniversity of Michigan Medicine Department of Ophthalmology & Visual SciencesDepartment of Health Management & PolicyChief Data OcerSight Outcomes Research Collaborative (SOURCE)Ernst Tamm, MD, FARVOVice President for Research and Support for Emerging Academics, University of RegensburgProfessor and Chairman Institute of Human Anatomy & Embryology Janey L. Wiggs, MD, PhD, FARVOPaul Austin Chandler Professor of OphthalmologyVice Chair for Clinical Research in OphthalmologyCo-Director, Glaucoma Center of ExcellenceHarvard Medical SchoolAssociate Director, Ocular Genomics InstituteAssociate Director, Howe LaboratoryAssociate Chief for Ophthalmology Clinical ResearchAssociate Member, Broad Institute of Harvard and MITSenior Scientist, Massachusetts Eye and Ear Barbara Wirostko, MDClinical Adjunct Professor Ophthalmology/Visual Sciences Moran Eye Center, University of UtahAdjunct Professor, Dept. of BioengineeringUniversity of UtahDonald J. ZackJohns Hopkins University School of MedicineINDUSTRY LIAISONSBaldo Scassellati Sforzolini, MD, PhD, MBAGlobal Head of R&D GaldermaNaj Sharif, BSc (Jnt Hons), PhD, DSc, FARVO, FBPhSVice PresidentGlobal Alliances & External Research (GAER)Global Ophthalmology R&DSanten Inc. USA

ZEISS Glaucoma Work owDetecting disease early and managing progression reliably.Assess & educateZEISS CLARUS 500: The  rst fundus imaging system to provide true color and clarity within an ultra-wide  eld of view, enabling clinicians to capture high-resolution fundus images from macula to the far periphery.ZEISS SL 800 with ZEISS SL Imaging Solution: ZEISS takes your everyday slit lamp exams to the next level by adding the integration of high-quality image and video capture to exam reports, off ering you the ability to document cases, including patient education, teaching or publishing.Plan ZEISS CIRRUS 6000: The next-generation OCT from ZEISS, delivering high-speed image capture with high-de nition imaging detail and a wide  eld of view.ZEISS HFA3 Perimeter: The gold standard of perimetry, with SITA Faster expanded testing options and reduced patient test times.Treat ZEISS ARTEVO 850: Surgical microscopes from ZEISS for excellence in optics, illumination and ergonomics. ZEISS CALLISTO eye markerless technology available. ZEISS VISULAS combi: First fully integrated therapeutic laser workstation off ering photodisruption and photocoagulation technology without compromise. CheckZEISS Glaucoma Workplace: Analyze side-by-side progression data from ZEISS CIRRUS OCT and ZEISS HFA at a glance. The Progression Summary display intelligently con gures the Structure-Function Guided Progression Analysis (GPA™) to show speci cally where change (OCT) or progression (perimetry) has been detected. * The link directs to an International website. This site features our entire product portfolio worldwide. The products featured may not be available in the US. Please contact your local representative for more information.CAP-en-US_31_035_0078II © Carl Zeiss Meditec, Inc., 2025. All rights reserved.Not all products, services, or off ers are approved or off ered in every market and approved labeling and instructions may vary from one country to another. For country-speci c product information, see the appropriate country website. Product speci cations are subject to change in design and scope of delivery as a result of ongoing technical development.Contact your ZEISS representative to discuss how ZEISS Glaucoma Work ow can help you streamline your practice and provide a better patient experience. And for more about our products and solutions visit: zeiss.com/glaucomawork ow.*PART OF THE ZEISS MEDICAL ECOSYSTEM Assess & educateTreatPlan Check

© 2025 Sight Sciences. Sight Sciences and the Sight Sciences logo are registered tardemarks of Sight Sciences. 03/2025 SS-3167-US.v2Sight Sciencesis a proud sponsor of The Glaucoma Foundation.We congratulate all the honorees and celebrate The Glaucoma Foundation’s 41st anniversary! At Sight Sciences, we share a similar vision. We have embarked on a mission to develop transformative, interventional technologies that allow eyecare providers to procedurally elevate the standards of care – empowering people to keep seeing.

New World Medical’s mission is to preserve and enhance vision by delivering innovations to ben-efit humanity. With a strong fo-cus on surgical glaucoma, our innovative portfolio includes the Ahmed® Glaucoma Valve (AGV), Ahmed ClearPath®, KDB GLIDE®, STREAMLINE® Surgical System and VIA360™ Surgical System. With an unwavering commitment to quality and global access, we develop products that provide long-lasting, often life-changing benefits to a person’s eyesight and well-being.The Ahmed® Glaucoma Valve is designed for patients with severe glaucoma. As a leader in glauco-ma drainage for over 30 years, the AGV is more than an implant — it’s a proven solution. Its unique features include a nonobstruc-tive valve system that eectively reduces and controls intraocular pressure. The Ahmed ClearPath® 250 and 350 are valveless drain-age devices that oer flexibili-ty and a natural fit for patients, giving ophthalmologists options based on patient needs.For patients with early-stage glau-coma, the KDB GLIDE® provides precision in excising diseased trabecular meshwork for Primary Open Angle Glaucoma, making it ideal for both standalone and combined cataract surgeries. The STREAMLINE® Surgical Sys-tem is a first-line, implant-free solution developed in collabo-ration with ophthalmologists. It allows precise viscoelastic injec-tions during standalone and com-bined cataract surgeries, empow-ering surgeons to leave only their best work behind. The VIA360™ Surgical System oers single entry, on demand viscoelastic delivery with intui-tive features that enhance both control and comfort, improving the overall surgical experience. VIA360 can be used in combina-tion with cataract surgery or as a standalone procedure, ultimately oering flexibility to the surgical workflow.In addition to our commitment to innovation, we uphold a strong dedication to philanthropy. Through the Sidra Tree Foun-dation, we work to democratize eye care globally by investing in healthcare systems in developing nations. Our investments ensure our mission to improve vision ex-tends beyond product innovation to make a lasting impact on com-munities worldwide. NEW WORLD MEDICALLearn more about our mission and innovative solutions at www.newworldmedical.com

SHATTERING THE STATUS QUOINTERVENTIONAL GLAUCOMAiDose TR is a long duration intracameral procedural pharmaceutical that delivers prostaglandin analog therapy for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension.1The catalyst to advance the interventional glaucoma revolution, helping you and your patients take back control of their treatment journey. Actual size 1.8mm x 0.5mm ©2024 Glaukos Corporation. All rights reserved. iDose TR and Glaukos are registered trademarks of Glaukos Corporation. PM-US-1761INDICATIONS AND USAGEiDose TR (travoprost intracameral implant) is indicated for the reduction of intraocular pressure (IOP) in patients with open angle glaucoma (OAG) or ocular hypertension (OHT).IMPORTANT SAFETY INFORMATIONDOSAGE AND ADMINISTRATIONFor ophthalmic intracameral administration. The intracameral administration should be carried out under standard aseptic conditions.CONTRAINDICATIONSiDose TR is contraindicated in patients with active or suspected ocular or periocular infections, patients with corneal endothelial cell dystrophy (e.g., Fuch’s Dystrophy, corneal guttatae), patients with prior corneal transplantation, or endothelial cell transplants (e.g., Descemet’s Stripping Automated Endothelial Keratoplasty [DSAEK]), patients with hypersensitivity to travoprost or to any other components of the product.WARNINGS AND PRECAUTIONSiDose TR should be used with caution in patients with narrow angles or other angle abnormalities. Monitor patients routinely to conrm the location of the iDose TR at the site of administration. Increased pigmentation of the iris can occur. Iris pigmentation is likely to be permanent.ADVERSE REACTIONSIn controlled studies, the most common ocular adverse reactions reported in 2% to 6% of patients were increases in intraocular pressure, iritis, dry eye, visual eld defects, eye pain, ocular hyperaemia, and reduced visual acuity.Please see full Prescribing Information. You are encouraged to report all side effects to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. You may also call Glaukos at 1-888-404-1644.1. iDose TR (travoprost intracameral implant) 75 mcg Prescribing Information. Glaukos Corporation. 2023.View full prescribing information at iDoseTRhcp.com

The honoree for this year’s awards dinner is Dr. Alon Harris. He will be receiving the Robert Ritch Award for Excellence and Innovation in Glaucoma. At Topcon Healthcare, we are honored to support The Glaucoma Foundation and celebrate Dr. Harris’s outstanding contributions to preserving vision and improving patient care.©2025 Topcon Healthcare, Inc | topconhealthcare.comTopcon Healthcare, Inc. Proudly CongratulatesAlon Harris, MS, PhD, FARVOProfessor of Ophthalmology, Professor of Articial Intelligence & Human Health, Vice Chair of International Research and Academic Affairs, Director of Ophthalmic Vascular Diagnostic & Research Program, Co-Director of the Center for Ophthalmic Articial Intelligence & Human Health at Mount Sinai Hospital, New York, NYExcellence and Innovation in GlaucomaROBERT RITCH AWARD

Service for Sight

Professor Alon Harrisis honored to congratulateon receiving the2025 Robert Ritch Awardin recognition of his exceptionalcontributions to glaucoma researchand his enduring commitment to theadvancement of vision science.We can’t think of a more deservingleader, innovator, and friend!Congratulations!

Not an actual patient.BRIDGE THE GAPFOR REFRACTORY GLAUCOMA WITH MINIMALLY INVASIVE FILTERING SURGERY CONSIDER XEN® FOR THE NEXT STOP ON YOUR PATIENT’S TREATMENT JOURNEY. XEN® Gel Stent is a proven pathway to IOP control for refractory glaucoma patients.1 • From a wide range of baseline pressures,* XEN® Gel Stent achieved a mean IOP of 15.9 (± 5.2) mm Hg through 12 months (n = 52)1, 2 • 76% of XEN® Gel Stent patients achieved a ≥ 20% IOP reduction in the ITT group (N = 65)1• 81% of XEN® Gel Stent patients achieved a ≥ 25% IOP reduction among those completing the 12-month visit (n = 52)2• Pivotal safety data included 0% intraoperative complications (0/65) and 0% persistent hypotony (0/65); transient hypotony† occurred in 24.6% of patients (16/65)1IOP = intraocular pressure; ITT = intent to treat. * In the XEN® Gel Stent clinical study, baseline medicated IOP ranged from 20.0 to 33.7 mm Hg.2 † No clinically significant consequences were associated with hypotony, such as choroidal effusions, suprachoroidal hemorrhage, or hypotony maculopathy. IOP < 6 mm Hg was defined as an adverse event, regardless of whether there were any associated complications or sequelae related to the low pressure. Thirteen cases occurred at the 1-day visit; there were no cases of persistent hypotony, and no surgical intervention was required for any case of hypotony.1INDICATIONS The XEN® Glaucoma Treatment System (XEN® 45 Gel Stent preloaded into a XEN® Injector) is indicated for the management of refractory glaucomas, including cases where previous surgical treatment has failed, cases of primary open-angle glaucoma, and pseudoexfoliative or pigmentary glaucoma with open angles that are unresponsive to maximum tolerated medical therapy.IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS XEN® Gel Stent is contraindicated in angle-closure glaucoma where angle has not been surgically opened, previous glaucoma shunt/valve or conjunctival scarring/pathologies in the target quadrant, active inflammation, active iris neovascularization, anterior chamber intraocular lens, intraocular silicone oil, and vitreous in the anterior chamber.WARNINGS XEN® Gel Stent complications may include choroidal effusion, hyphema, hypotony, implant migration, implant exposure, wound leak, need for secondary surgical intervention, and intraocular surgery complications. Safety and effectiveness in neovascular, congenital, and infantile glaucoma has not been established. Avoid digital pressure following implantation of the XEN® Gel Stent to avoid the potential for implant damage.PRECAUTIONS Examine the XEN® Gel Stent and XEN® Injector in the operating room prior to use. Monitor intraocular pressure (IOP) postoperatively and if not adequately maintained, manage appropriately. Stop the procedure immediately if increased resistance is observed during implantation and use a new XEN® system. Safety and effectiveness of more than a single implanted XEN® Gel Stent has not been studied.ADVERSE EVENTS The most common postoperative adverse events included best- corrected visual acuity loss of ≥ 2 lines (≤ 30 days 15.4%; > 30 days 10.8%; 12 months 6.2%), hypotony IOP < 6 mm Hg at any time (24.6%; no clinically significant consequences were associated, no cases of persistent hypotony, and no surgical intervention was required), IOP increase ≥ 10 mm Hg from baseline (21.5%), and needling procedure (32.3%). Caution: Federal law restricts this device to sale by or on the order of a licensed physician. For the full Directions for Use, please visit www.allergan.com/xen/usa.htm or call 1-800-678-1605. Please call 1-800-433-8871 to report an adverse event.Please see full Directions for Use at https://www.rxabbvie .com/pdf/xen_dfu.pdf© 2024 AbbVie. All rights reserved. All trademarks are the property of their respective owners.US-XEN-240031 04/2024 025426References: 1. XEN® Directions for Use. 2. Grover DS, Flynn WJ, Bashford KP, et al. Performance and safety of a new ab interno gelatin stent in refractory glaucoma at 12 months. Am J Ophthalmol. 2017;183:25-36. doi:10.1016/j.ajo.2017.07.023.

Regeneron Pharmaceuticals, Inc. C O N G R A T U L A T E S Dr. Alon Harris, MS, PhD, FARVOProfessor of Ophthalmology, Professor of Artificial Intelligence & Human Health, Vice Chair of International Research and Academic Affairs, Director of Ophthalmic Vascular Diagnostic & Research Program, Co-Director of the Center for Ophthalmic Artificial Intelligence & Human Health at Mount Sinai Hospitalfor receiving the Dr. Robert Ritch Award for Excellence and Innovation in GlaucomaREGENERON IS PROUD TO SUPPORT THE 29TH ANNUAL GLAUCOMA FOUNDATION THINK TANKRegeneron is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for over 35 years by physician-scientists, Regeneron’s Founded and led for over 35 years by physician-scientists, Regeneron’s unique ability to repeatedly and consistently translate science into medicine has led to numerous FDA-approved treatments and product candidates in development, almost all of which were homegrown in Regeneron’s laboratories. Regeneron’s medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, hematologic conditions, infectious diseases, and rare diseases.conditions, infectious diseases, and rare diseases.

Regeneron Pharmaceuticals, Inc. C O N G R A T U L A T E S Dr. Alon Harris, MS, PhD, FARVOProfessor of Ophthalmology, Professor of Artificial Intelligence & Human Health, Vice Chair of International Research and Academic Affairs, Director of Ophthalmic Vascular Diagnostic & Research Program, Co-Director of the Center for Ophthalmic Artificial Intelligence & Human Health at Mount Sinai Hospitalfor receiving the Dr. Robert Ritch Award for Excellence and Innovation in GlaucomaREGENERON IS PROUD TO SUPPORT THE 29TH ANNUAL GLAUCOMA FOUNDATION THINK TANKRegeneron is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for over 35 years by physician-scientists, Regeneron’s Founded and led for over 35 years by physician-scientists, Regeneron’s unique ability to repeatedly and consistently translate science into medicine has led to numerous FDA-approved treatments and product candidates in development, almost all of which were homegrown in Regeneron’s laboratories. Regeneron’s medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, hematologic conditions, infectious diseases, and rare diseases.conditions, infectious diseases, and rare diseases.

Thea Pharma Inc. recognizes the continuous pursuit of The Glaucoma Foundation as it continues to support research and education aimed at improving life and vision for millions of glaucoma patients.We join you in honoring the accomplishments of Dr. Alon Harris as the recipient of the Robert Ritch Award.Thea_TGF_FP-ad_PRC-EN-2432-v2 05-2025.indd 1Thea_TGF_FP-ad_PRC-EN-2432-v2 05-2025.indd 1 5/14/25 9:06 AM5/14/25 9:06 AM