Leo A. Kim, MD, PhD, and his team put his unique hypothesis to the test with a boost from philanthropic support. Now, they may be onto a promising treatment for pulmonary fibrosis, one of the most common lung complications caused by COVID-19.
At the start of the COVID-19 pandemic in the spring of 2020, all “non-essential” laboratories not involved in the response to the virus at research hospitals like Mass Eye Ear were ordered to shut down. That included the lab of Dr. Leo Kim, a physician-scientist who specializes in treating and researching retinal disorders.
Dr. Kim and his colleague Joseph Arboleda-Velasquez, MD, PhD, had been studying new treatments for common eye diseases such as age-related macular degeneration, diabetic retinopathy and proliferative vitreoretinopathy. Their work was based off a discovery Drs. Kim and Arboleda-Velasquez made earlier in their careers that a protein called RUNX1 was involved in two processes seen in several of these eye diseases: the formation of abnormal blood vessels, called aberrant angiogenesis, and scar tissue, or fibrosis. Dr. Kim had recently worked on several papers that showed promise in using medications that inhibit the RUNX1 protein to treat eye diseases in animal models. The team one day hopes to test these in people. But this work would have to come to a halt last spring since it did not have any tie to COVID-19.
Like most scientists during this time, Dr. Kim was closely following COVID-19 research papers, when he noticed studies that found many patients with COVID-19 were experiencing a complication called pulmonary fibrosis. Pulmonary fibrosis causes tissue deep in the lungs to scar, and has been shown to be associated with abnormal blood vessel activity. In fact, there had been reports of blood vessel-related complications in COVID-19 patients, such as strokes and venous thromboembolism (VTE).
“As I was reading these papers I would think to myself, what are the odds? Two processes involved in COVID-19-related lung issues are ones that I work on trying to stop inside the eye,” Dr. Kim recently told Focus. “I wondered whether RUNX1 might be involved.”
Putting the theory to the test
Dr. Kim wanted to explore this question more since he already had tools in the lab to examine angiogenesis and fibrosis in the eye. But he needed some help. He turned to Michel Plantevin, a donor who had supported Dr. Kim’s earlier research. Michel generously donated to the effort. With this funding and with Dr. Kim able to reopen his lab after shifting its focus to COVID-19 research, he quickly got to work.
“That funding was monumental to get us started,” said Dr. Kim. “I really appreciate Michel’s support. He gambled on just an idea. But these ideas can be transformative, and we would never know unless we test them.”
Reopening the lab was not so simple. First, Drs. Kim and Arboleda-Velasquez had to reassemble their team. One pivotal member, postdoctoral research fellow Hannah Whitmore, PhD, had returned to the United Kingdom at the start of the pandemic. Dr. Kim had to appeal to get her special re-entry access through the U.S. Embassy in London with a letter provided by Dr. Patricia D’Amore, associate chief for Ophthalmology Basic and Translational Research at Mass Eye and Ear. They then had to safely get the postdoctoral fellows and research associates to and from the lab each day. Thanks to the funding, they were not only able to support the research, but also organize daily ride shares for each lab member.
With the team in place, they next needed to obtain RUNX1 inhibitor medications for testing. A scientist from the National Institutes of Health came through, developing some from scratch. Next, they turned to a research lab in Germany to evaluate tissue samples from COVID-19 subjects. Scientists were coming together to help this study move forward.
“We had to go through extraordinary measures to study this connection, unlike anything I’ve ever had to do in my career,” said Dr. Kim.
The team also recruited David Lagares, PhD, a scientist at the Fibrosis Research Center at Mass General Hospital to assist. With these pieces in place, next came the most important question– will this actually work?
Promising treatment target identified
In a new study published in The American Journal of Pathology, Drs. Kim and Arboleda-Velasquez validated the hypothesis that RUNX1 was playing a role in the formation of pulmonary fibrosis related to COVID-19. What’s more, they found that the same drug they’d been testing to inhibit RUNX1 in eye disease may do the same for this serious lung complication.
The researchers conducted their study using mouse models and human lung tissue. They saw the RUNX1 inhibitors prevented pulmonary fibrosis by blunting the mechanisms that led to the formation of scarring and blood vessel-mediated inflammation. Remarkably, RUNX1 inhibition also reduced the expression of two “host proteins” critical for getting the SARS-CoV-2 virus into cells, called ACE2 and FURIN. These findings suggested that RUNX1 inhibitor drugs may be beneficial as both a treatment and preventive therapy. They could treat pulmonary fibrosis after infection, and fight back against COVID-19 by reducing the chances of the virus getting into lung cells and vessels in the first place.
“COVID-19 is first and foremost a disease caused by an individual’s response to a virus. In some cases, the infection causes no symptoms, whereas in others, the same virus causes severe disease or is lethal,” explained Dr. Arboleda-Velasquez. “We need more drugs like RUNX1 inhibitors that address the host response to the virus in clinical trials if we want to beat COVID-19.”
Their findings can be particularly impactful, as some studies have found 40 percent of COVID-19 patients may have acute respiratory distress syndrome (ARDS), which can lead to pulmonary fibrosis. This complication is not only seen in severe cases, but also in many “long hauler” patients who recover. Current treatments for pulmonary fibrosis, however, only slow its progression, and do not effectively stop the disease.
The RUNX1 inhibitor used in this study was previously tested in patients in a phase 2 clinical trial years ago for the treatment of HIV. At the time, the drug was not effective at blocking HIV infection, but was found to be safe for patients. This drug has yet to be approved by the Food and Drug Administration, and would require more study to do so. Yet, Dr. Kim feels given its proven safety, that an RUNX1 inhibitor would be an ideal candidate to accelerate into a clinical trial for pulmonary fibrosis. Their hope is to generate enough interest among the scientific community to make this clinical trial a reality.
“We considered ourselves underdogs and had a lot of skeptics, even I was skeptical,” said Dr. Kim. “We’ve gotten this far, and the next step is a clinical trial to test a RUNX1 inhibitor.”
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