In this plaque assay, the cell culture has been stained purple so that the infectious SARS-CoV-2 particles, or virions, can be seen clearly. The circles represent single infectious virions that have poked holes in the cell culture.

The race to identify U.S. Food and Drug Administration (FDA)-approved drugs that can be repurposed to prevent or treat COVID-19 is advancing toward the finish line, under a $6.3 million federal grant that was recently awarded to Benjamin tenOever, PhD, Irene and Dr. Arthur M. Fishberg Professor of Medicine, Icahn Professor of Microbiology, and Director of the Virus Engineering Center for Therapeutics and Research (VECToR) at the Icahn School of Medicine at Mount Sinai.

Dr. tenOever’s lab is currently testing a group of 20 promising drugs that were narrowed down from thousands over the course of several months by teams led by Donald Ingber, MD, PhD, at the Wyss Institute for Biologically Inspired Engineering at Harvard University, and Matthew Frieman, PhD, at the University of Maryland School of Medicine. All three institutions are working together under a one-year $16 million umbrella grant from the U.S. Defense Advanced Research Projects Agency (DARPA).They have created a full drug-testing pipeline with the goal of finding effective treatments for COVID-19 or prophylactics that prevent the SARS-CoV-2 virus from entering human cells. None exist at this time.

The institutional collaboration loosely resembles a relay race, with a baton that has now been passed from Harvard and the University of Maryland to Dr. tenOever’s lab.

“Both groups have provided me with a small list of drugs from their respective screens, with quite a bit of overlap, and we will decide together and with DARPA to prioritize the ones that are the most promising,” says Dr. tenOever. “We are running the last set of tests here.” The drugs have all been FDA-approved for a range of different treatments.

Members of Benjamin tenOever’s lab, postdoctoral fellow Ben Nilsson-Payant, PhD, left, and PhD candidate Skyler Uhl, enter Mount Sinai’s Biosafety level 3 laboratory to begin testing the SARS-CoV-2 virus in a batch of drugs that may protect against viral replication.

Each participant in the DARPA grant has contributed to a specific leg of the drug-discovery process. The Wyss Institute provided the human organ chip technology. The University of Maryland provided high-throughput screening. And Mount Sinai is testing the drugs in animal models using the actual virus.

Currently, Dr. tenOever’s lab is testing the drugs in lung organoids—tiny replicas of the human lung that are composed of multiple cell types. In July, his lab will begin to test the drugs in a more sophisticated human organ chip technology, which was developed by a Wyss Institute spinoff, Emulate, Inc. After that, Dr. tenOever’s lab will test the finalists in animal models.

He says his timeline is flexible. Largely, it depends on how quickly his lab finds something that appears to be really promising. “If we find a drug that looks fantastic, then we will probably focus on that one and learn everything we can about it and start a human trial because it’s already FDA-approved. But if none of the first batch of drugs work, we move onto the next batch,” Dr. tenOever says. “In cell culture, some drugs look like miracles. But when you move them into more complex systems like human organ chips, things really fall apart. Just because a drug works in cells doesn’t mean it works in animals. That’s exactly the kind of situation we want to avoid and exactly what my lab is trying to parse out.”

The goal of the DARPA project is to find drugs that can be used in the very early stages of the disease cycle to either prevent the virus from entering cells or dismantle the virus before it has a chance to replicate in the lungs. The drugs being tested in Dr. tenOever’s lab would focus on the early aspects of the disease prior to the respiratory complications of COVID-19. Once that occurs the disease is more about inflammation than viral infection and, for that reason drugs such as dexamethasone would be used to diminish inflammation.

Individuals with Down syndrome, the nation’s most common genetic disorder, represent a small, vulnerable segment of the U.S. population whose comorbid conditions may make them particularly susceptible to severe forms of COVID-19.

In fact, people with Down syndrome who are over the age of 30 appear to be about nine times as likely as the general population to be hospitalized for COVID-19, and their hospital stays tend to be more than twice as long, with a median of 17 days, according to a recent study from the Icahn School of Medicine at Mount Sinai that was uploaded onto the pre-print server medRxiv. Approximately 250,000 people in the United States have Down syndrome.

“When you don’t have a critical mass of people who are able to advocate for themselves, which is the case with Down syndrome, then people start falling through the cracks,” says the study’s senior author, Dusan Bogunovic, PhD, Associate Professor of Microbiology, and Pediatrics, and Director of the Center for Inborn Errors of Immunity, which is part of the Mindich Child Health and Development Institute. “We did not want that to happen. We felt that particular attention should be paid to the prevention and treatment of COVID-19 in individuals with Down syndrome.”

From left: Dusan Bogunovic, PhD, and Louise Malle, MD/PhD candidate

Dr. Bogunovic and MD/PhD candidate Louise Malle led a research team that examined the electronic medical records of 4,615 patients with COVID-19 who were hospitalized within the Mount Sinai Health System. They expected to find one or perhaps even two patients with Down syndrome based on the syndrome’s low prevalence within the population. Instead, they identified six adults, all of whom were in their 50s except for one, who was in her 30s. Two of the six patients, both in their 50s, succumbed to the disease. By comparison, Dr. Bogunovic says, 2 out of 30 cases were fatal in an age, sex, and race-matched control group of people who did not have Down syndrome.

Four of the six Down syndrome patients with COVID-19 were also diagnosed with sepsis, which is a marker of extreme inflammation, according to Ms. Malle. The individuals with Down syndrome were more likely to be hospitalized in an intensive care unit and to have been placed on a ventilator. In addition, she says, a constellation of other health issues associated with Down syndrome, such as autoimmune disease, epilepsy, and dementia, may have played a role in the severity of COVID-19. Further studies will be needed to determine whether these patients were more likely to produce higher levels of inflammatory markers.

Over the past 20 years, improved health care for individuals with Down syndrome has led to increased longevity, with many now living into their early 60s. That however, is still roughly 20 years shorter than individuals without the disorder. The median age of the hospitalized patients with Down syndrome was 54, roughly 12 years younger than the rest of the population that was hospitalized as a result of the disease.

Dr. Bogunovic says one positive finding was that “none of the patients we looked at were pediatric patients, so it does follow the trend of the general population that the older you are the more likely you are to be hospitalized with COVID-19.” He adds that the current study points to the need for “additional research into the medical conditions of marginalized patients with rare genetic conditions,” particularly during a pandemic.