Carol M. Troy, MD, PhD, leads a team of investigators based at Columbia University Irving Medical Center (CUMC) that is a XSeed Award Finalist for work to develop the first noninvasive treatment for retinal vascular occlusion, the sight-threatening blockage of a vein in the light-sensitive inner layer of the eye. The novel medication is designed to be given as eyedrops. Troy is Professor of Pathology and Cell Biology and of Neurology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC.
The XSeed Award provides critical funding to translate scientific discoveries into commercially successful drug therapies. The 2024 XSeed awards will provide two winning teams up to $250,000 for New York City minority- and women-led life science and healthcare startups working on novel drug development projects. The winners will be announced in September 2024.
This conversation has been edited for length and clarity.
Cure: What is retinal vascular occlusion?
Carol Troy: Retinal vascular occlusion (RVO) is the second leading cause of retinal vascular disease in working-age people and is most often caused by diabetes and high blood pressure. In RVO, there is decreased blood flow in the retina due to blockage of one or more retinal veins, prohibiting the outflow of blood and leading to edema, inflammation, impairment of neuronal function and vision loss.
RVO is a global challenge. For example, cohorts of young men in India, in particular, who are hypertensive and smokers have a high incidence of RVO, and they are going blind.
Cure: How is RVO currently treated?
Troy: The main RVO treatment is medicines that target vascular endothelial growth factor (VEGF) that are given by injection directly into the eye by a physician. But many people around the world do not have access to anti-VEGF therapies.
In addition, about 50 percent of patients don't respond to anti-VEGF treatment. Among those who do, 20 percent of them stop responding and continue to develop vision loss
Cure: What is the new treatment you have developed and how does it work?
Troy: RVO increases the activity of an enzyme called caspase-9, and this activation in retinal endothelial cells is critical for RVO to progress. The new therapy is called Pen1-XBir3. It works by inhibiting the caspase-9. Pen1-XBir3 is a dual agent. Pen1 allows for topical delivery to the eye, and XBir3 targets and blocks the activity of caspase-9.
Cure: How did you come up with this idea?
Troy: I am a neurologist and pharmacologist by training. I became very interested in how the neurovascular unit was affected in disease. We have the opportunity to actually see the neurovascular unit in action when we study the retina, because you can look into a patient’s eye without having to do surgery.
Blindness is a major healthcare issue. While working on a model of stroke in the brain, we identified certain mechanisms that prompted us to ask if other neurovascular diseases, like RVO, were associated with similar mechanisms. So, we turned to the retina and worked on our mouse model of RVO. We identified caspase-9 as an enzyme that is activated in stroke and leads to cell death. We also designed a cell-permeable inhibitor of caspase-9.
Cure: What has your laboratory research demonstrated so far?
Troy: In our mouse model of RVO, we knocked out endothelial cell caspase-9 and observed that the mice were protected from RVO. They had reduced edema and inflammation, less neuronal death and improved visual function.
We published a paper where we compared Pen1-XBir3 with a standard-of-care anti-VEGF therapy in our mouse model. We examined the mice using imaging called optical coherence tomography (OCT) and found that Pen1-XBir3 eyedrops were equal or superior to anti-VEGF injections, resulting in a reduction in edema, ischemia and vision loss.
Also, Pen1-XBir3 was superior to the anti-VEGF treatment in protecting the neurons. Over time with anti-VEGF therapies, the retina thins due to the death of neurons, which may be what is happening in the 20 percent of patients who stop responding to those treatments. Pen1-XBir3 saved more neurons.
Cure: How often might the eyedrops be given? And can you explain why eyedrops are preferred to injections as a treatment for RVO?
Troy: We haven't worked out the dosing yet, but it would need to be a dosing schedule that is easy for patients to remember — like once a day, once a week, or once a month. They can give eyedrops to themselves in their own homes, on their own time. In comparison, anti-VEGF injections, are given in a doctor's office once every month or two.
A significant amount of time and money goes into getting an anti-VEGF injection — not just for the patient, but for the person taking them to the appointment, who also may have to take off of work. And the patient has to stay in the office for four hours after the injection. So, anti-VEGF injections can be inconvenient and costly.
Cure: If you win the XSeed Award, what would that mean for this project?
Troy: With the XSeed Award funds, we would conduct two experiments in the lab. In one experiment, we would analyze the mouse retinas we collected from our prior studies to gain a better understanding of the molecular differences between eyes that did or did not do well with Pen1-XBir3 versus anti-VEGF treatment. This will help us understand who might benefit most from Pen1-XBir3.
In the second study, we would validate the effectiveness of Pen1-XBir3 in human retinal tissue (from people who donated their eyes for corneal transplants after death) and refine the dose response. We would treat the tissue and then see how the doses we used in the mouse model translate to humans.
Cure: What motivates you to keep moving this work forward?
Troy: Visual impairment has enormous effects on quality of life. It can lead to sensory deprivation. Sometimes patients with RVO have dementia or develop it after their RVO diagnosis. The physician side of me wants to get this to patients because there is nothing like this out there for them. They call my office to ask about it. Sometimes it's a family member who helps them contact me.
The worst is when a patient says, "My daughter dialed the phone because I can't do that anymore." There are patients asking for something different, something more than what we can currently provide. Clinical trials would give us the first opportunity to do that.
Cure: Who is on your team?
Troy: My team includes two coinvestigators in Columbia University’s Department of Ophthalmology: Tongalp Tezel, MD, the Chang Family Endowed Professor of Ophthalmology and the Director of the Vitreoretinal Service and Fellowship Program, and Chloe Li, MD, an Ophthalmology resident who researches human retinal disease.