CFC4: The Melza M. and Frank Theodore Barr Foundation Catalyst for a Cure Initiative to Prevent and Cure Neurodegeneration

Launched in July 2022, the fourth in Glaucoma Research Foundation’s Catalyst for a Cure series pursues one of our most confounding medical challenges: how to prevent and cure diseases that, like glaucoma, Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), occur when key cells in the central nervous system deteriorate and die — a process known as neurodegeneration.

CFC4 advances a transformative discovery by the first Catalyst for a Cure team: that glaucoma, long considered a disease of the eye, is actually a neurodegenerative illness. Although neurodegenerative illnesses are increasing in prevalence, treatments that protect, repair, or regenerate neurons remain elusive. By bringing together innovative investigators whose paths would not otherwise cross, the CFC model provides unique potential for outside-the-box scientific creativity — the kind of high-risk/high-reward research that rarely wins support from traditional funders.

STATUS
Initiated in 2022. Currently funded through 2025.

GOALS
Explore similarities and differences among glaucoma and other conditions that stem from the death of neurons in the eye, brain, or spinal cord, in search of potential preventive measures and cures for all neurodegenerative illnesses.

INVESTIGATORS

Sandro Da Mesquita, PhD
Assistant Professor, Department of Neuroscience
Meningeal Lymphatics and Neurological Disorders Lab
Mayo Clinic
Dr. Da Mesquita’s unique expertise is in the field of brain vascular biology, which has implications for Alzheimer’s and other neurodegenerative diseases.

Milica Margeta, MD, PhD
Physician and Surgeon
Massachusetts Eye and Ear
Assistant Professor of Ophthalmology
Harvard Medical School
Dr. Margeta is a glaucoma clinician and surgeon and a leader in the biology of microglia (unique cells of the brain and spinal cord) and in neuroinflammation.

Karthik Shekhar, PhD
Assistant Professor, Department of Chemical and Biomolecular Engineering
Faculty Scientist, Lawrence Berkeley Laboratory
Member, Helen Wills Neuroscience Institute
University of California Berkeley
A leader in computational biology, Dr. Shekhar has played a key role in collaborations that span neuroscience, immunology, single cell genomics, genetics, and machine learning, with a focus on visual systems.

Humsa Venkatesh, PhD
Assistant Professor, Program in Neuroscience
Brigham and Women’s Hospital
Harvard Medical School
Dr. Venkatesh’s discoveries have shaped the emerging field of cancer neuroscience, illuminating the nervous system’s role in disease progression.

RESULTS
The four investigators for the Neurodegeneration Initiative met in person for the first time in July 2022 to kick off their collaboration. Their initial priority is to identify promising avenues of exploration, drawn from their areas of expertise, that could reveal how and why neurons die — the first step toward preventing and curing neurodegeneration.

CFC3: The Steven and Michele Kirsch Catalyst for a Cure Vision Restoration Initiative

Glaucoma is a complex disease in which damage to the optic nerve leads to progressive vision loss. Today’s treatments, which work by lowering pressure in the eye, can only preserve remaining vision. They don’t improve or restore vision that already has been lost to glaucoma.

Restoring vision in patients with glaucoma has been a tremendous challenge. As part of the central nervous system, the optic nerve cannot regenerate itself naturally after injury. Consequently, scientists seeking vision restoration solutions must find innovative ways to regrow or replace retinal ganglion cells and axons, which make up the optic nerve.

STATUS
Initiated in 2019. Currently funded through 2024.

GOALS

• Preserve the optic nerve, independent of eye pressure
• Repair the optic nerve, independent of eye pressure
• Rebuild the optic nerve where damage has already resulted in vision loss

INVESTIGATORS

Xin Duan, PhD
Assistant Professor, Department of Ophthalmology and Physiology
Weill Institute for Neurosciences
University of California, San Francisco
Dr. Duan’s laboratory investigates retinal ganglion cells subtype-intrinsic factors and tests their roles in optic nerve regeneration and vision recovery.

Yang Hu, MD, PhD
Associate Professor, Department of Ophthalmology
Stanford University School of Medicine
Stanford, CA
The Hu laboratory focuses on the mechanisms responsible for neuronal degeneration and axon regeneration while maintaining a consistent focus on clinically relevant scenarios and therapies that will translate into effective vision restoration treatments.

Anna La Torre, PhD
Associate Professor, Department of Cell Biology and Human Anatomy
School of Medicine, University of California, Davis
Davis, CA
Dr. La Torre’s laboratory focuses on generating retinal ganglion cells from stem cells to enhance axonal growth and cell survival and ultimately, to use these cells as donor cells for cell replacement therapies and disease modeling.

Derek Welsbie, MD, PhD
Associate Professor of Ophthalmology, San Diego Shiley Eye Institute
University of California, San Diego
San Diego, CA
The Welsbie lab focuses on identifying genes that are causally involved in retinal ganglion cell death, degeneration, and regeneration, as well as developing new neuroprotective drug therapies for retinal ganglion cells.

RESULTS
Promising leads are already emerging from the collaboration of vision restoration investigators. In late 2021, the team reported dramatic progress in two areas: developing therapies to transplant retinal ganglion cells and exploring ways to preserve and enhance the eye’s neurological connections. As their collaboration continues, investigators will continue to refine their approaches to retinal ganglion cell transplantation using various glaucoma models, both retina and optic nerve, and test treatments they have already identified to improve the survival of cells. They are moving ever closer to therapeutic approaches for the human eye that, ultimately, can be tested in clinical trials.

CFC2: The Biomarker Initiative

A biomarker is an early indicator of disease, often identified on a cellular level. Finding new biomarkers for glaucoma could help predict the disease or diagnose it earlier, before patients show symptoms; enable doctors to tailor treatment to individual patients; and speed the development of new therapeutic targets to preserve vision.

Chosen for their particular expertise in biomedical imaging, physics, retinal cell biology, neurobiology, and clinical ophthalmology, members of the second Catalyst for a Cure consortium set out to identify changes in the retinal ganglion cells that are first affected in glaucoma, before any vision is lost.

STATUS 
Initiated in 2012. Completed in 2018.

GOALS

• Identify and develop new, specific and sensitive biomarkers, paving the way for novel methods to detect, measure, and treat glaucoma with unprecedented precision.

INVESTIGATORS

Alfredo Dubra, PhD
Associate Professor of Ophthalmology
Stanford University School of Medicine
The main goal of the Dubra lab is to develop non-invasive optical imaging methods for early detection and monitoring of eye disease. The lab pursues a multidisciplinary approach, with a major focus on translating techniques and analytical tools from physics, astronomy and mathematics into robust quantitative diagnostic tools.

Jeffrey L. Goldberg, MD, PhD
Professor and Chair, Department of Ophthalmology
Stanford University School of Medicine
Dr. Goldberg’s research is directed at neuroprotection and regeneration of retinal ganglion cells and other retinal neurons. His laboratory is developing novel stem cell and nanotherapeutics approaches for ocular repair, studying retinal ganglion cell development, survival and axon regeneration in glaucoma, and investigating the cellular basis for the developmental loss of axon growth ability.

Andrew D. Huberman, PhD
Associate Professor, Departments of Neurobiology and Ophthalmology
Stanford University School of Medicine
The purpose of the Huberman laboratory is to research and understand how the retinal and brain circuits that underlie vision wire up during development and to develop new strategies to monitor, prevent, and treat retinal ganglion cell loss in glaucoma. Dr. Huberman is a neuroscientist who has made many contributions to the brain development, brain plasticity, and neural regeneration and repair fields. 

Vivek Srinivasan, PhD
Associate Professor of Biomedical Engineering, Ophthalmology & Vision Science, and Chancellor’s Fellow, University of California, Davis
Department of Biomedical Engineering, Davis, California
The Srinivasan Biophotonics Laboratory develops novel optical imaging techniques and diagnostics with applications spanning from basic to clinical research. In particular, the lab is interested in neuronal control of hemodynamics and metabolism both in health and disease in the central nervous system, including the retina and brain. Their highly interdisciplinary approach combines cutting edge imaging technologies with collaborations ranging from neurobiology to neurology and ophthalmology to test fundamental hypotheses and explore the diagnostic implications.

RESULTS

Conducting a detailed, systematic analysis of retinal ganglion cells (RCGs), partners found one subtype that changes its shape much earlier in the disease. They then developed techniques to identify whether these and other potential candidate biomarkers may signal early changes that lead to vision loss.

Moving from the laboratory to the clinic, team members tested their top biomarker candidates and used computers and virtual reality to develop potential new non-drug therapies. CFC2 research has already resulted in at least two new clinical trials to protect vision. With funding from the National Eye Institute, the four individual scientists are continuing their important research initiatives.

CFC1: The Inaugural Initiative

With much to be discovered in the quest for a cure for glaucoma, Glaucoma Research Foundation launched its first Catalyst for a Cure initiative with the conviction that collaboration among leading scientists from diverse disciplines could initiate transformative progress. Participants were chosen for their particular expertise in neurobiology, ophthalmology and developmental genetics. To ensure a fresh perspective and bring new ideas to accelerate a cure, the consortium included specialists who were not previously studying glaucoma. This team of pioneers’ findings have redefined our understanding of how glaucoma steals sight and opened the door for new therapeutic approaches to the disease.

STATUS
Initiated in 2002. Completed in 2012.

GOALS

• Advance a multidisciplinary approach to identify the risk factors and biological origins of glaucoma, define new diagnosis and therapy targets, and move closer to a cure.
• Explore glaucoma on the molecular levels, with an emphasis on genetics and neurodegeneration of the optic nerve.

INVESTIGATORS

David J. Calkins, PhD
Vice-Chairman and Director of Research;
Denis M. O’Day Professor of Ophthalmology and Visual Sciences, Neuroscience and Psychology
Director, Vanderbilt Vision Research Center
Vanderbilt Eye Institute, Nashville, Tennessee
The Calkins lab focuses on the mechanisms of neurodegeneration in glaucoma. Using systems, cellular and molecular approaches, they investigate how risk factors contribute to neurodegeneration and test new treatments. Dr. Calkins specializes in molecular mechanisms of the retina and optic nerve.

Philip J. Horner, PhD
Professor of Neuroregeneration, Institute for Academic Medicine
Scientific Director, Center for Neuroregeneration
Houston Methodist, Weill Cornell Medical College
Houston, Texas
The Horner lab is focused on neurodegeneration and neural regeneration in models of glaucoma and spinal cord injury. The lab established a reliable glaucoma model that helped the team to study and test hypotheses. Dr. Horner’s experience in spinal cord injury and glial cells, applied to glaucoma, led to new findings on the role of gliosis and oxidative stress in glaucoma.

Nicholas Marsh-Armstrong, PhD
Associate Professor, Department of Ophthalmology and Vision Science
University of California, Davis
Davis, California
The Marsh-Armstrong laboratory studies molecular mechanisms involved in gene regulation, development and disease of the central nervous system, focusing principally on the retina. Marsh-Armstrong has identified gamma-synuclein aggregates in glaucoma in the CFC model of glaucoma — an important finding relating glaucoma to other neurodegenerative diseases.

Monica L. Vetter, PhD
Professor and Chair, Department of Neurobiology and Anatomy
University of Utah
Salt Lake City, Utah
The Vetter lab is studying glaucoma at the molecular level to understand how genetics influence and determine the fate of neurons in the retina and central nervous system. Their goal is to reveal principles governing cell biology that will lead to new disease treatments. Dr. Vetter is committed to better understanding the role of microglia in retinal ganglion cell pathology in glaucoma.

RESULTS

The first CFC delivered promising results on two fronts: preventing vision loss from late-stage glaucoma, and therapeutic treatment to stop glaucoma before it starts. One of the team’s most important accomplishments was the discovery that the first impacts of glaucoma show up not in the eye but in the visual centers of the brain, among tiny energy batteries in the nerves, known as mitochondria. This discovery led to the identification of a window of opportunity for preventing vision loss in the early stages of glaucoma progression, when optic nerve fibers are attempting to repair themselves.

Findings like these form the basis of the team’s revelation that glaucoma is not just a condition of the eye; it is a neurodegenerative disease in the same family as Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS). Research results published by the first CFC team have resulted in nearly 8,000 citations by other scientists.