Avi Ma’ayan, PhD

As the public turns its attention to vaccine development in the hope of ending the COVID-19 pandemic, equally important work is taking place in the area of drug repurposing—identifying drugs already approved for other diseases that may also be effective for COVID-19. Repurposed drugs offer a safe and relatively quick and inexpensive treatment route.

At the Icahn School of Medicine at Mount Sinai, a team of researchers led by Avi Ma’ayan, PhD, Director of the Mount Sinai Center for Bioinformatics and Professor of Pharmacological Sciences, is investigating drugs with the most potential. To that end, they created the COVID-19 Drug and Gene Set Library, a crowdsourced database and website that consolidates information from multiple labs around the world that performed in vitro COVID-19 drug screens. These in vitro tests are performed in a petri dish, which is the first stage in drug discovery, before the drugs are tested in animal models and then in human clinical trials. The website is available to all scientists who want to compare drug screen “hits,” and has drawn 2,000 viewers since it was launched in April.

“Drugs are just as important as vaccines and offer a solution for dealing with this pandemic,” says Dr. Ma’ayan. “The hope is that we’ll find a drug, or a combination of drugs, that people can take after they’re infected with the virus to block the virus from spreading and enable them to mount an effective immune response.” After all, he adds, not everyone may be eligible to receive a vaccine, based on their health profile, and even with a vaccine there will be people who get COVID-19 and need treatment.

Venn diagram shows some overlap in a set of drugs relevant to COVID-19 research

In September, the journal Patterns, a Cell Press publication, published an article that described the Ma’ayan Laboratory’s work on the project. The article described the lab’s machine learning approach, which explored approximately 200 “positive hit” drugs that were identified as inhibiting the SARS-CoV-2 virus, which causes COVID-19, from infecting human cells in vitro. Based on the shared biological and chemical properties of these drugs, the machine-learning model prioritized these drugs further and predicted additional compounds with similar properties.

“When you start synthesizing data from multiple studies, you look for consistency and seek to identify interesting mechanisms,” he says. “We want to understand the mechanism of action of those drugs. Why do they work? What are the pathways they affect? What are the targets of those drugs so we can better understand the lifecycle of the virus?” Currently, the laboratory led by Benjamin tenOever, PhD, Director of the Virus Engineering Center for Therapeutics and Research at the Icahn School of Medicine at Mount Sinai, is conducting experiments to further explore some of these questions in collaboration with Dr. Ma’ayan.

According to Dr. Ma’ayan, the COVID-19 Drug and Gene Set Library organizes information in a way that can be clearly summarized and reused at a crucial time in COVID-19 research, when time is of the essence. The library allows the scientific community to work together toward a cure and avoid promoting drugs that are not fully validated, which happened last spring with hydroxychloroquine.

“The website that we built is supposed to be unbiased,” he says, “and it looks at evidence in a way that offers consistency across the studies, where the right answer comes up in a more distributed, democratic way.”

When considering promising drugs Dr. Ma’ayan points to the example of HIV, a virus for which there is no vaccine, but many combinations of drugs that effectively keep the viral load very low and prevent new infections. These drug “cocktails” have helped improve the lives of many people around the world. “There are fewer people dying from HIV because of these drugs,” he says. “It’s not guaranteed we’ll have a vaccine for COVID-19 that’s 100 percent effective or even 50 percent effective, and there are people who aren’t going to be able to receive the vaccine. If people get sick from COVID-19 and you have drugs that can treat them, you could turn it into a disease that more people can recover from.”

Men who were hospitalized for COVID-19 in New York City during the early days of the pandemic were both younger and healthier on average than their female counterparts, according to a new study by researchers at the Icahn School of Medicine at Mount Sinai. The study, posted to the preprint server medRxiv, analyzed the electronic health records of 3,086 racially diverse COVID-19 patients who were admitted to five hospitals within the Mount Sinai Health System on or before April 13, 2020, and followed through June 2, 2020.

“Just being male seemed to be a risk factor in and of itself,” says the study’s first author, Tomi Jun, MD, a hematology and medical oncology Fellow at The Tisch Cancer Institute of the Mount Sinai Health System. Members of Mount Sinai’s Department of Genetics and Genomic Sciences, and Scientific Computing and Data Science, also contributed to the study.

Of those requiring hospitalization, 59.1 percent were male with a median age of 64, vs. 74 years of age for women. While the men were more likely to have a history of smoking, the women were more likely to have pre-existing comorbidities such as hypertension, diabetes, chronic obstructive pulmonary disease and asthma, and obesity. The mortality rate for men and women was equal.

Tomi Jun, MD

“This was during the early days when there was a surge of cases in New York and we did not have effective treatments,” says Dr. Jun. “Looking at the data, there were a disproportionate number of men being hospitalized. And these men seemed to be healthy enough to do well with COVID-19, because we know that older age and having more comorbidities are associated with worse outcomes. When you take all those things into account, being male seemed to increase your risk.”

Kuan-lin Huang, PhD, Assistant Professor of Genetics and Genomic Sciences, and the study’s senior author, says, “We know there are a lot of hormonal and immunological differences between men and women. There are certain genes on the X chromosome that are involved in the immune system and women have two X chromosomes. Women go through pregnancy, which can have strong effects on the immune system. And we know that women are at higher risk of developing an autoimmune disease. Likely, it’s a complex set of these factors that contributed to the results. Specifically what is it? I don’t think anyone knows for sure. But that is what we were trying to get closer to with this and subsequent studies.” Understanding the underpinning of why this is happening at the molecular level, he adds, will provide insights into potential treatments.

Kuan-lin Huang, PhD

The researchers found interesting results when they examined data about the patients’ blood. “COVID-19 is very inflammatory and all of the hospitalized patients had very high markers of inflammation,” says Dr. Jun. “But we observed that women tended to have lower markers of inflammation than men. We conducted exploratory analyses to look at how predictive these markers were for death and found that in some cases higher markers for inflammation were associated with higher risk in women than men. So, although women, in general, had less inflammation than men when they entered the hospital, having higher indicators of inflammation seemed to confer a greater risk for them.”

Dr. Huang says the current study is a jumping-off point for future investigations that was made possible by Mount Sinai’s policy of allowing its data and clinical scientists to access the electronic health records.

“If our hospitals hadn’t taken care of all these patients and we didn’t know their histories we wouldn’t be able to do this research,” he says. “We really hope this will lead to more precise patient management. We should have different considerations for men and women when we think about whether that may add on to the risk of a COVID-19 patient.”

Supinda Bunyavanich, MD, MPH, and post-doctoral fellow Scott Tyler, PhD. File photo.

On Saturday, March, 14,  as the U.S. economy was beginning to shut down due to the COVID-19 pandemic, Supinda Bunyavanich, MD, MPH, a mother of two young children and a Professor of Genetics and Genomic Sciences, and Pediatrics, at the Icahn School of Medicine at Mount Sinai, had a “eureka” moment.

“I was at home thinking about the world and how New York City was being hit, and I realized so much is unknown about this virus,” Dr. Bunyavanich recalls. As a parent, Dr. Bunyavanich says she was relieved to read that children appeared to be less susceptible to catching COVID-19 than the rest of the population based on reports from China, although no one knew precisely why.

Dr. Bunyavanich was on the phone that day with Alfin Vicencio, MD, Chief of Pediatric Pulmonology at the Icahn School of Medicine at Mount Sinai. They discussed how the SARS-CoV-2 virus, which causes COVID-19, might enter the body through ACE2 receptors—proteins on the surface of many cells, including those found in the lining of the nose. At that moment, she realized she had important data that connected both lines of research.

“I thought, ‘wait a minute,’ ” Dr. Bunyavanich says. “COVID-19 is a respiratory condition. I have data on what’s happening in the noses of people of many ages from my studies of asthma. Could it be that kids have fewer access points for the virus to enter?’”

In May, JAMA published the novel findings from Dr. Bunyavanich’s data, which showed that lower ACE2 expression in children relative to adults may help explain why the disease is less prevalent in young children.

“The degree to which we express ACE2 may play into how susceptible we are to the SARS-CoV-2 virus,” Dr. Bunyavanich says. “Our finding that there are age-related differences in the level of ACE2 is consistent with epidemiologic data from around the world that children suffer less from COVID-19. Lower nasal expression of ACE2 in children is a concrete finding from our study that might explain why children are less affected by SARS-CoV-2.”

Interestingly, Dr. Bunyavanich’s data are from a Mount Sinai study she has been leading for a few years that looks for nasal biomarkers for asthma. The data, part of a study of 305 individuals between the ages of 4 and 60, includes “an atlas of genes that a person expresses in their nose,” she says. “The original project wasn’t targeted to ACE2, but we had this library of information on hand, so we homed in on ACE2 given its potential role in COVID-19.”

The researchers found that young children have the least expression of ACE2 in their nasal passages and that the quantity increases with age, so that children 10 to 17 years of age have more than younger children, but less than young adults age 18 to 24. The highest level was found in individuals 25 and older.

It is possible, she says, that young children have plenty of virus particles in their noses, but perhaps they are less likely to enter the body. “Think of ACE2 as a doorknob that SARS-CoV-2 uses to get in. There might be plenty of virus waiting to get through the door, but it has a harder time compared to adults,” she says. “The virus won’t cause illness if it can’t get in.”

According to Diana W. Bianchi, MD, Director of the National Institute of Child Health and Human Development, young children tend to be mildly affected by COVID-19, and relatively few end up in intensive care units. Their symptoms also present differently than those in adults, with diarrhea, abdominal pain, and other gastrointestinal problems.

Many questions surrounding children and COVID-19 continue to be the focus of widespread debate, particularly as communities consider whether to reopen schools in the fall.

“In-person learning versus virtual learning is such a complicated topic,” says Dr. Bunyavanich. “For every family it’s going to require a different set of considerations about risk versus benefits and what their preferences are. Even though children are less susceptible overall, susceptibility might vary between individual children, and it’s still possible for children to carry the virus. You have to think of the whole web of complex interactions children have. That’s what makes it so hard.”