FORT WORTH – Could existing treatments be repurposed to treat COVID-19 patients?
It all began from a hypothesis that Mohanakrishnan Sathyamoorthy, M.D., the department chair of Internal Medicine at the Fort Worth medical school, started developing in early March that focused on a different aspect of treating the cytokine storm that leads to the deadly inflammation in many COVID-19 patients.
“I realized that this couldn’t be a solo project; this is a medical school level effort,” Dr. Sathyamoorthy said. “The best way to think about how we can serve our community, science and medicine at large would be to create a working group.”
Over the next few weeks, Dr. Sathyamoorthy had conversations with Stuart D. Flynn, M.D., the founding dean of the medical school, about which faculty members and physicians across the Dallas-Fort Worth area might be interested in the research.
“This is our time and opportunity here in Fort Worth and we know this,” Dean Flynn said. “We’ve set up this environment to build a much bigger attraction to industry to want to come in here and do their clinical trials. That is the ultimate goal.”
Following those conversations , Dr. Sathyamoorthy set out to recruit the top specialists in North Texas to work on the research.
“From that point, I began recruiting individuals one-on-one who could bring a level of scientific, clinical and collaborative acumen to contribute to the culture of this working group,” Dr. Sathyamoorthy said.
By mid-April, the Fort Worth Clinical Sciences Working Group was formed. It is comprised of 15 physicians in leadership roles at major North Texas hospital systems such as Baylor, Scott & White, Texas Health Harris Methodist Hospital, JPS Health Network, Cook Children’s Hospital and the medical school. The physicians in the group represent a range of medical specialties that include infectious diseases, transplant immunology, cardiovascular medicine, pulmonary critical care medicine, pediatric critical care medicine and pediatric oncology and immunology.
To get the ball rolling, three of the physicians in the group took a look at Dr. Sathyamoorthy’s initial eight-page hypothesis and provided feedback. Afterwards, they created a new draft of the hypothesis and circulated among the entire group for a peer review.
Within the working group there are subgroups focused on tasks such as fundraising, an institutional review board subcommittee (IRB) and a writing group.
“Since then, we have met nearly 30 times (via Zoom) as a working group and also in subgroups that were created,” Dr. Sathyamoorthy said.
By mid-August the group had developed three new proposals around COVID-19 that they planned to study. The first is the treatment of the cytokine storm that COVID-19 causes in the human body that leads to the deadly inflammation.
A simple way of thinking about how this happens is looking at how a virus invades the human body and how the body normally responds.
“When they (cytokines) work correctly, they are working every day for us clearing organisms out of our body and we never know it,” Dean Flynn said.
In the case of COVID-19, the human body has never seen this virus before. The body begins to try and create the appropriate immune response using those typically helpful cytokines to eliminate the virus. But over time the immune response becomes unregulated and unchecked, Dr. Sathyamoorthy added.
“The cytokine storm is this horrible state that leads to unchecked and unregulated inflammation (in the human body),” Dr. Sathyamoorthy. “In some patients, there is a dysregulation of intensity of this inflammatory response and the result is you actually end up damaging your own tissue.”
In an effort to eliminate the virus, the immune response by your body can end up damaging important heart tissue and lung tissue that can ultimately lead to death in some patients.
“There’s a lot of intense effort around this and all of us keep track of the literature,” Dr. Sathyamoorthy said. “We are learning that the human genome and genetic predispositions to this inflammatory response are playing a big role among many other potential factors.”
Dean Flynn spent many years as a pathologist and cancer researcher. When he began looking at Dr. Sathyamoorthy’s hypothesis, he was intrigued by the role genetics might play in inflammatory responses presented in some COVID-19 patients.
“I’m going to bet that we are going to find some genetic differences among those who get really sick and among those who look like the same patient that doesn’t get sick that’s very intriguing,” Dean Flynn said.
If that bet holds true, it will be phenomenal news for a major collaborative partner in this research group. Illumina, a company known as a global leader in genomics, which is an industry at the intersection of biology and technology are also partnering with the school of medicine in this research effort.
“Because of what we do in the education realm in genomics they were intrigued with how we could work together,” Dean Flynn said. “They want to look at the same things we want to look at and they want to see.”
Illumina is interested in seeing if the patient base put together by the research group can find genetic differences that might start to be predictive of how COVID-19 reacts in different ethnic groups.
“They are in the world of genetic sequencing but they are also in the world of showing the value of this sequencing and we’ve opened the door for them to take advantage of this study,” Dean Flynn said.
The second area of their research looks at currently available off-the-shelf treatments that can be repurposed to treat inflammation caused by the cytokine storm. Those will be monoclonal antibodies targeting Th1 cytokines that are responsible for the cell-mediated immune response the human body produces against viruses.
“The consensus to date has been to target Th2 (cytokines) and we’re going in a different direction.” Dr. Sathyamoorthy said. “There were studies published in July in Nature medicine and Science immunology that looked at the cytokines and inflammatory profiles in patients with COVID-19 that were very sick and symptomatic. It turns out that the cytokines that we are targeting (Th1) are the cytokines that are most highly expressed in the sickest patients. All of the physicians in the working group were pretty jazzed up to see those papers posted.”
This area of the research also takes a look into clotting, which is another common symptom of COVID-19 patients.
“Patients come in with these unexplained clotting events whether it is strokes, clots in their legs or clots in their arterial circulation,” Dr. Sathyamoorthy said. “We used a hypothesis driven effort to study what treatment may have the best impact on managing that clotting.”
The final component is the creation of a city-wide biorepository proposal.
“That will be critically important to many ventures related to this project and future projects,” Dr. Sathyamoorthy said. “Creating a biorepository of prospectively labeled samples that we can come back and analyze retrospectively is a big part of our goal.”
The research group has already taken the idea to Floyd Wormley, Jr., Ph.D., the associate dean for research and graduate studies at Texas Christian University and received approval. They will be able to store some of their research specimens inside of freezers in TCU’s research labs in the future, according to Dean Flynn.
“Everyone here has had an open-door policy and wanted to help. Everyone is excited. This is cool stuff for Fort Worth,” Dean Flynn said.
The timing of the research group’s formation fits with medical school’s curriculum for its newest group of medical students. They will be learning about cytokines this Fall semester. There will be opportunities for some of the new medical students to help the group in their research efforts.
“They will get the basic information of how these cytokines work, which is a beautiful thing,” Dean Flynn said. “This whole issue of cytokines, cytokine storms and clotting – they are all intimately related.”
The value this brings to the educational experience for the medical students is two-fold. The opportunity to take small portions of the research and help out in their spare time could ultimately become a part of their four-year Scholarly Pursuit & Thesis, which is a requirement for each student.
“Boom. They’ve not only got their four-year thesis, they also are really valuable to the research group,” Dean Flynn said.
Before the group can move forward with their research and begin clinical trials, they will need to get a few things done. They are currently applying for Food and Drug Administration (FDA) exemptions to be able to repurpose currently available drugs in a new way to battle COVID-19.
“As you could imagine, there is a huge binder of things that need to be constructed to send to the FDA to see if we can get the permission to complete the study,” Dr. Sathyamoorthy said.
The group’s IRB subcommittee will also need to get approval from the IRB’s at multiple hospitals across North Texas.
“We’re working closely with Baylor’s IRB right now which is the first hospital we’re working with,” Dr. Sathyamoorthy said. “Soon, we will deploy across the other IRB’s in the city including Texas Health Harris Methodist Hospital and JPS Health Network. So, getting through this part of the process takes time.”
As the COVID-19 pandemic continues to affect people across the world, the research group is dedicated to being a part of the solution.
“To be able to leverage this type of model and template as a structure to foster the next line of hypothesis and questions that could be transformative in the future, and is already pretty awesome,” Dr. Sathyamoorthy said. “But if our hypothesis can lead to one improved life or one saved life then what we have demonstrated in Fort Worth is a model that could be adopted across so many other communities.”
Watch Video FWMD LIVE: COVID-19 Research Group
Stuart D. Flynn, M.D., the Founding Dean of the TCU and UNTHSC School of Medicine and Mohanakrishnan Sathyamoorthy, M.D., the department chair of Internal Medicine at the School of Medicine shared information about the medical school’s new COVID-19 research group during a chat on FWMD LIVE on Wednesday, September 30.
During the discussion they both shared information about their new research team organized by the TCU and UNTHSC School of Medicine called the Fort Worth Clinical Sciences Working Group. Both of our medical experts answered questions about what areas of COVID-19 their research will focus on, COVID-19 vaccine trials, what the research will mean for medical students and hospital systems in North Texas and much more.