Our research
Focused on glaucoma, we investigate ocular development and ocular biology with the goal of improving care. This includes studies of intraocular pressure, ocular drainage biology and neurodegeneration. We have a strong interest in metabolism, nutrition, and lifestyle-based interventions to increase cellular resilience against disease and trauma.
Our laboratories are located at the Department of Ophthalmology at Columbia University Irving Medical Center and at the Zuckerman Mind Brain Behavior Institute.
GLAUCOMA👁️
Glaucoma is a common neurodegenerative disease that leads to the death of neural cells. It is a major cause of blindness, affecting 80 million people worldwide, and is often associated with elevated pressure within the eye itself, called intraocular pressure (IOP).
This harmful pressure damages retinal ganglion cells (RGCs) and results in neurodegeneration. The molecular processes that raise IOP and damage RGCs are only partially understood.
Glaucoma is a complex disease. Multiple distinct processes and pathways play a role in glaucoma. Further research is needed to better understand the disease and develop improved treatment strategies. This includes developmental or congenital glaucomas that are difficult to treat and are one of our research foci.
OUR MISSION🚀
To provide a new molecular understanding of glaucoma to improve treatment options and prevent disease. A major goal is the development of safe, metabolism-supporting interventions and nutritional supplements.
OUR VISION💡
We use mouse models as a powerful system for determining mechanisms and testing treatments. A variety of advanced technologies, including single-cell RNA-seq, help to drive our research. Our program integrates genetics, genomics, cell biology, molecular biology, physiology, mitochondrial/ metabolism, and nutrition-based interventions to understand, treat and prevent glaucoma. We identify new genes, pathways, and disturbed processes that lead to high IOP and/or glaucoma. We translate this knowledge into new treatments through clinical trials. Additionally, we collaborate to develop and test miniature devices to enhance research and monitor/treat disease.
RESILIENCE-BASED NEUROPROTECTIVE TREATMENTS
We are determining how high IOP damages retinal neurons and we are developing new resilience-boosting treatments that either target IOP, retinal neurons, or both. Our new, resilience-centered, approaches adjust or restore cellular metabolism and/or increase other cellular resources that protect from stress. This enhances the ability of ocular tissues to fend off disease, and if applied sufficiently early may even prevent disease development.
Existing interventions aim to lower IOP, but fail to either address the underlying mechanisms or to prevent IOP elevation or glaucoma from developing in the first place. Current treatments do not work adequately for all patients, and in some patients glaucoma may continue to progress despite successful lowering of IOP.
Our studies in mice discovered alterations of NAD, a central molecule in energy metabolism, in glaucoma, as well as disturbed glucose and pyruvate metabolism. We demonstrated that dietary supplementation with vitamin B3 (nicotinamide) can strongly prevent glaucoma. Vitamin B3 is precursor of NAD. We further showed that pyruvate protects from glaucoma, while supplementation with both vitamin B3 and pyruvate is more effective than either alone. This opened the door for ongoing clinical trials using these resilience-boosting metabolites with initial promising outcomes.
UNMET MEDICAL NEED IN CHILDHOOD GLAUCOMA
Although existing IOP treatments are impactful, patients are still going blind. Developmental or childhood glaucomas are particularly difficult to treat. There is concern about the potential systemic side effects of current medications in these very young patients, while there is a need for treatments to both succeed and be tolerable over a lifetime. The difficulty of administering eye drops and the risks of anesthesia and infection from surgery are also higher in young children. Our ongoing studies on eye development and childhood glaucoma are supporting the establishment of new treatment strategies.
Our early-stage data implicate disturbed metabolism and stress responses in disease initiation and progression. This suggests that metabolism-supporting, resilience-boosting treatments may be effective in these conditions. Our preliminary treatment data in mice support this.
Although this work is ongoing, success could lead to a new paradigm of using dietary or other metabolic interventions to augment treatment approaches and improve outcomes. The successful development of safe, effective, dietary treatment and prevention strategies would be a major advance against childhood glaucoma.
CLINICAL IMPACT
Our discoveries in mice have encouraged clinical trials worldwide with initial promising results. Some of these trials test the effect of nicotinamide or nicotinamide riboside alone, but recently, a clinical study at Columbia tested the combination of oral nicotinamide and pyruvate. In an initial short-term trial, this resulted in an improvement of visual function in patients with glaucoma. Further clinical studies are being carried out to test for longer-term effects and optimize the dose.
GENE THERAPY
Gene therapy and genome editing technologies are advancing rapidly, with the promise to help against IOP elevation and glaucoma. Gene therapies can be developed so that they are either highly targeted to individuals or more generally applicable to wider patient populations. Of these options, resilience-based and metabolism-supporting gene therapies are more generally applicable to more patients.
Illustrating the promise of the resilience approach, we demonstrated that retinal gene therapy using an enzyme (NMNAT1) involved in the conversion of vitamin B3 into NAD potently protects mice from a chronic glaucoma. The protection was even greater when combined with nutritional supplementation with vitamin B3.
Effective gene therapy requires a safe and efficient method of delivering therapeutic genes to the target cells. Viral vectors, such as adeno-associated viruses (AAVs), are commonly used to deliver therapeutic genes to specific tissues in the eye. AAV vectors need to be developed: 1. To specifically target Schlemm's canal, an important vessel for ocular drainage and IOP. 2. To specifically target a cell type known as astrocytes in the optic nerve head.
Ongoing work is aimed at developing such vectors and we have a future interest in non-viral strategies.
DIET, LIFESTYLE, AND GLAUCOMA
As part of our resilience-boosting strategy, we are interested in the effects of diet and lifestyle on glaucoma. Modulating diet and lifestyle may have an important influence on the effects of our metabolism-supporting and nutrient-based interventions as well as on conventional treatment outcomes. A healthy diet and exercise are shown to protect from other diseases and aging, including neurodegenerative diseases. Further research in this area is warranted.
ROLE OF VASCULATURE IN GLAUCOMA
We and others have determined that multiple insults and cell types contribute to glaucoma. Blood vessels are important in supplying nutrients and oxygen to cells to support metabolism and in removing breakdown products.
The endothelial cells that line blood vessels are also central in modulating the entry of inflammatory cells into stressed tissues. In the central nervous system, endothelial cells also contribute to the formation of the blood-brain barrier and blood-retinal barrier, which prevent neurotoxic molecules from entering these tissues. We have demonstreted endothelial chages that allow monocytes to enter the optic nerve head in glaucomatous mice and modulate disease. An ongoing project investigates the roles of IOP and blood vessels in glaucoma.
OVERVIEW OF SOME OF OUR PROJECTS
Here is a sneak peek into some of our ongoing projects. Check out our publications to learn more about what we do.
1. Understanding aqueous humor dynamics and IOP elevation. We use single-cell and other genomic, transcriptomic, and metabolic experiments to better understand the molecular control of aqueous humor drainage and how IOP becomes elevated with age and in glaucoma.
2. Studying the development of ocular drainage tissues and developing dietary interventions for childhood glaucomas. Abnormal formation of the eye results in childhood and early-onset glaucoma, which can manifest at different ages. Ocular drainage structures (trabecular meshwork and Schlemm's canal) are located in a region of the eye called the angle, and angle abnormalities contribute to IOP elevation. We have studied several genes and processes that contribute to childhood and early-onset glaucomas. We are defining the developmental and transcriptomic sequences that control the formation of the ocular drainage tissues and contribute to developmental glaucomas with the use of single-cell sequencing techniques and other advanced methods. We are discovering that perturbed metabolism and cell stress responses contribute to pathogenesis, with dietary-based metabolic interventions offering new treatment avenues. These studies are also highly relevant for adult glaucomas, since genes responsible for developmental glaucoma can be involved in adult forms of the disease.
3. Unraveling the functional morphology of the ocular drainage pathways. This effort closely integrates with other trabecular meshwork and Schlemm's canal studies, but with an emphasis on microanatomy and changes with differing pressures. We use recent microscopic innovations (in confocal microscopy, 3D EM, nanoCT, etc.) and we are developing an organ culture system to characterize the functional anatomy of the drainage tissues and to determine the roles of specific molecules in defined cell types and processes.
4. Roles of different cell types in glaucoma and development of dietary/metabolism-supporting treatments. We are investigating the roles of different cell types such as vascular cells and astrocytes in RGC and optic nerve degeneration in glaucoma. We aim to determine how aging, metabolic, and epigenetic changes in different cell types modulate vulnerability to glaucoma. Projects include single-cell resolution omic technologies, the study of axon degeneration pathways, how the blood-retinal barrier becomes compromised in glaucoma, and determining how metabolism changes with age and glaucoma. We have a particular interest in the development of resilience-boosting treatments that enhance cellular bio-energetics and anti-stress processes.
5. Designing gene therapies against glaucoma. We are working to improve viral vectors and other non-viral methods for gene delivery. We are also using ATAC-seq and other methods to provide deeper understanding of gene regulatory mechanisms in glaucoma relevant cell types. This will lead to improved control of gene therapies (improved control, specificity and safety).
TRAINING
Training is also an important component of our program, with trainees obtaining hands-on experience while conducting research projects. Our approach is multidisciplinary with projects involving diverse expertise including clinical evaluation, genetics, genomics/gene expression (single-cell sequencing, spatial transcriptomics, etc.), gene therapy, molecular biology, pathology, physiology, neurobiology, microscopy, imaging, and metabolomics/metabolism. We are generating large, complex datasets that require data science/biostatistics and innovative computational analyses. This provides a fertile training environment with laboratory members progressing to top graduate and medical programs. After completing their training, almost all of our postdoctoral trainees have obtained faculty positions with the others obtaining appropriate high-level scientific positions of their choice. We are always interested in considering dedicated, high-caliber candidates at various career stages.
