Research | Mount Sinai Today

Mount Sinai Physicians Create an Effective Road Map for Treating COVID-19

Nov 5, 2020 | COVID-19, Featured, Research

Carlos Cordon-Cardo, MD, PhD

Experts at the Mount Sinai Health System have created a road map for clinicians to follow when providing care to COVID-19 patients, which characterizes four distinct stages of the COVID-19 disease cycle and outlines specific testing and treatment protocols for them. The new approach—called staging—is featured in the latest issue of Cancer Cell and is modeled after the way in which cancer and other complex diseases, such as chronic renal disease, are managed.

“COVID-19 parallels other very difficult diseases in that it manifests specific clinical phases of progression,” says the study’s corresponding author, Carlos Cordon-Cardo, MD, PhD, the Irene Heinz Given and John LaPorte Given Professor and Chair in Pathology, at the Icahn School of Medicine at Mount Sinai. “In the absence of clear guidance we thought staging this disease could help physicians navigate better by linking the right tests to the most appropriate interventions. We want to give patients a better chance of being cured based on objective laboratory data and clinical information that is appropriate at different stages of the disease.”

The study lists stage 1 as viral entry; stage 2 as viral dissemination; stage 3 as multi-system inflammation (severe); and stage 4 as endothelial damage, thrombosis, and multi-organ dysfunction (critical), which affects a minority of patients. The study authors draw comparisons between the spread of the SARS-CoV2 virus, which causes COVID-19, within the body, and the spread of cancer, which metastasizes throughout the body—both resulting from disease-producing agents that create a cascade of dysfunction.

Staging requires knowing more about the patient than simply whether they tested positive or negative for COVID-19. Physicians, and the community at large, would benefit from tests that would also offer an indication of the level of viral particles affecting the patient, either high or low; since a patient with a high viral load and comorbidities such as advanced age, hypertension, diabetes, and coronary artery disease would be at higher risk for a poor prognosis.

Visual Summary of COVID-19 Stages

Since the beginning of the pandemic, physicians have learned important lessons about giving treatments early in the disease cycle, when they are most effective. One example is convalescent plasma therapy, which is best given before the patient develops their own antibodies to COVID-19.

“Analogous to the way we treat cancer, COVID-19 treatments have to be adapted to the evolution of the disease,” says study author, Luis Isola, MD, Professor of Medicine (Hematology and Medical Oncology), and Pediatrics, at the Icahn School of Medicine at Mount Sinai. “Treatments that may be effective early on no longer impact late disease. Conversely, treatments that help patients with advanced disease may not help or be justifiable when they present with it.”

The study’s authors say it is important to have a systematic approach to COVID-19 diagnostics and treatments that would keep the disease from progressing in those who might develop severe cases. “The idea is for us to provide guidelines for people to understand that this is not a simple disease, but one that is more complex,” says Dr. Cordon-Cardo.

In May, Mount Sinai released an autopsy study of 67 individuals with COVID-19 who had been admitted to one of the Health System’s eight hospitals from March 20 to April 29. The study showed the degree to which COVID-19 can lead to excessive blood clots and multi-organ failure.

David Reich, MD, President and Chief Operating Officer of The Mount Sinai Hospital, and one the study’s authors, says, “We learned a huge amount from the autopsy and innovative laboratory data collected from the very large number of COVID-19 patients cared for in the Mount Sinai Health System. Synthesizing all of these data led to this staging concept that has the potential to help clinicians worldwide in their understanding of the stages of this disease and in guiding the appropriate use of emerging therapies.”

Mount Sinai’s road map would also help COVID-19 patients understand the state of their own health during the disease cycle. Cancer patients at stage 2, for example, understand the course of their disease will be easier than it would be at stage 3 or 4, when they would require more aggressive treatments. The same holds true for COVID-19.

Mount Sinai Researchers Streamline Patient Data to Find Patterns in COVID-19 Patients

Oct 29, 2020 | Artificial Intelligence, Featured, Research

Girish Nadkarni, MD

With the influx of patient data resulting from the SARS-CoV-2 pandemic, the Mount Sinai COVID Informatics Center is collaborating with London-based software company Clinithink to uncover key findings that can enable better treatment methods for COVID-19 patients.

Clinithink’s artificial intelligence platform, CLiX, processes large volumes of data from physician notes and documents within electronic health records, allowing providers to save time and effectively determine key information on patient conditions.

“We are currently using the platform to mine clinical documents in order to extract information to further our understanding of COVID-19 and its complexities, so we can determine the best course of action for individual patients,” said Girish Nadkarni, MD, Assistant Professor, Department of Medicine (Nephrology), Clinical Director of the Hasso Plattner Institute for Digital Health, and Co-Director of the Mount Sinai COVID Informatics Center.

Through the use of Clinithink’s platform “CLiX^TM unlock,” the COVID Informatics Center is creating risk scores for COVID-19 patient symptoms, sifting through data that has been stripped of any personal information to find patterns that can ultimately lead to new discoveries in COVID-19 treatment.

“Clinithink is enabling us to identify and distinguish the symptoms in hospitalized COVID-19 patients during admission, in order to determine if and when new symptoms are appearing during their hospitalization,” Dr. Nadkarni said.

The Icahn School of Medicine at Mount Sinai was the first academic institution in the nation to partner with Clinithink in 2016, its original use to accelerate the prescreening process to identify eligible candidates for clinical trials.

“The collaboration between Clinithink and Mount Sinai represents how novel research can be translated into clinical practice,” Chris Tackaberry, CEO of Clinithink, said. “We are delighted to see Mount Sinai extend the use of our platform as they continue to make breakthrough discoveries in COVID-19.”

The collaboration was facilitated by Mount Sinai Innovation Partners (MSIP), the technology commercialization engine at Mount Sinai.

“Collaborating with Clinithink improves the way we understand and serve our patients,” said Erik Lium, PhD, President of MSIP and Executive Vice President and Chief Commercial Innovation Officer at the Mount Sinai Health System. “We look forward to seeing how Dr. Nadkarni’s team leverages Clinithink to extend our knowledge about COVID-19, and potentially improve treatment and patient outcomes.”

Mount Sinai Gets $2.5 Million NIH Grant to Open New Avenues for Diabetes Treatment

Oct 8, 2020 | Diabetes, Featured, Research

Principal investigator Andrew F. Stewart, MD, Director of the Diabetes Obesity and Metabolism Institute and Irene and Dr. Arthur M. Fishberg Professor of Medicine, right, and Adolfo García-Ocaña, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease).

About 420 million people in the world have Type 1 or Type 2 diabetes, including 30 million in the United States, and all suffer from reduced numbers of beta cells, says Andrew F. Stewart, MD, Director of the Diabetes Obesity and Metabolism Institute and Irene and Dr. Arthur M. Fishberg Professor of Medicine at the Icahn School of Medicine at Mount Sinai. “There are 30 to 40 drugs on the market for diabetes, and none of them make beta cells regenerate,” he says. “Developing such a drug, and a precise way to deliver it, is our aim.”

A project led by Dr. Stewart recently received a $2.5 million, four-year grant from the National Institute of Diabetes Digestive and Kidney Disease, to support Mount Sinai researchers’ innovative efforts to regenerate insulin-producing beta cells that could lead to novel drugs for patients with diabetes.

Dr. Stewart’s team in 2015 identified the first potent human beta cell regenerative drug, harmine, which is in a class of drugs called DYRK1A inhibitors. They identified additional drugs that enhance the regenerative capabilities of harmine—TGF beta inhibitors in 2019, and GLP-1 receptor agonists in 2020. The new grant will support new efforts to develop a means to deliver these drugs precisely.

Robert J. DeVita, PhD, Research Professor of Pharmacological Sciences, and Director of the Medicinal Chemistry Core of the Drug Discovery Institute, and Chalada Suebsuwong, PhD.

“These drugs clearly are effective but also have the potential to cause unwanted effects outside the beta cell, so we now need a way to target the beta cell regenerative drugs to the beta cell,” says Dr. Stewart, principal investigator of the grant. “In lay terms, we have a UPS package to make your beta cells better, but we do not yet know the address to deliver the package.” There are potential strategies for delivering these “packages” by attaching them to a GLP-1 receptor agonist or a monoclonal antibody, each a widely used type of drug.

The current project is a collaboration among Dr. Stewart; Adolfo García-Ocaña, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease); Robert J. DeVita, PhD, Research Professor of Pharmacological Sciences, and Director of the Medicinal Chemistry Core of the Drug Discovery Institute; and Thomas Moran, PhD, Professor of Microbiology, and Director of the Center for Therapeutic Antibody Development.

The research has four aims: First, Dr. DeVita and his team are making TGF beta inhibitors that can be linked to other molecules targeting beta cells. Second, Dr. Moran is focused on making one such molecule, a monoclonal antibody, which can deliver the drugs to beta cells. Third, Dr. Stewart and Dr. DeVita will “conjugate” the drugs with the delivery methods to investigate which combinations work the best. And fourth, Dr. García-Ocaña will test the therapies on human beta cells in mice.

Thomas Moran, PhD, Professor of Microbiology, and Director of the Center for Therapeutic Antibody Development.

“We are excited about these collaborative and translational studies that link basic laboratory research with ultimate goal of treating patients. For the first time, we have a series of new molecules that could be effective for both major forms of diabetes,” Dr. DeVita says. “If successful, a new targeted molecule could be scaled up in the future for further drug development, with the potential to treat millions of people around the world.”

Dr. Stewart is the site principal investigator for another grant for the study of diabetes, obesity, and other metabolic disorders, which was recently renewed by the National Institutes of Health. That five-year, $9.5 million grant was awarded to support the Einstein-Mount Sinai Diabetes Research Center, a regional collaborative led by Jeffrey Pessin, PhD, the Judy R. and Alfred A. Rosenberg Professorial Chair in Diabetes Research at the Albert Einstein College of Medicine and principal investigator on the grant.

The Center was founded in 1976 and has long focused its efforts on minority and other underserved populations in the region. Five years ago, it expanded into a regional collaborative, partnering with Mount Sinai to increase its capacity to support research studies and services. “The idea of these center grants is to have a series of cores that allow us to help people who are doing research, to do it faster, better, and more cost-efficiently,” Dr. Stewart says. For example, at Mount Sinai a core providing expertise in immune technology is led by Dirk Homann, MD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease); and a human islet adenovirus core is led by Dr. García-Ocaña.

“The Center has provided a major boost to basic science and clinical diabetes and obesity research and training efforts at both Mount Sinai, Albert Einstein College of Medicine, and multiple other medical schools in the greater New York region,” Dr. Stewart says. “The Einstein team has been an extraordinary scientific partner.”

Mount Sinai Actively Recruits Volunteers From Hardest Hit Communities for COVID-19 Vaccine Trial

Oct 5, 2020 | COVID-19, Engagement, Featured, Research, Vaccines

WillieBenjamin Loadholt, right, undergoes a checkup from Kiwan Stewart, RN, at The Mount Sinai Hospital prior to receiving his second injection as a participant in the phase 3 clinical trial for Pfizer’s COVID-19 vaccine.

Participating in the Mount Sinai Health System’s clinical trial for the Pfizer COVID-19 vaccine has been deeply personal for New York City educator WillieBenjamin Loadholt. He says it has provided him with the opportunity to be proactive, to contribute to a potential solution that could put an end to the COVID-19 pandemic, which has been “devastating to the African American community.”

For months, Mr. Loadholt says, “Every time I would go on a friend’s Facebook page I would see, ‘We regret to announce the passing or the transition of this person or that person.’ A friend of mine owns a funeral home and they were doing so many funerals. This one’s mom passed away, or this one’s father or sister passed away. It was heartbreaking.”

So, in August, when a friend told him about the Pfizer COVID-19 vaccine trial at Mount Sinai, Mr. Loadholt was eager to sign up. “We want to know what’s going on,” he says. “People perish from a lack of knowledge. How can we avoid this? How can we get solutions for this?” Participating in the search for answers to the COVID-19 pandemic is “worthwhile because I am able to help myself as well as my community. We can’t get this if we don’t help each other.”

Mount Sinai is actively recruiting volunteer participants in communities of color. “We want to make sure the trial is representative of the people who were hardest hit by COVID-19,” says Debbie Lucy, Program Manager for the Mount Sinai Health System’s COVID Clinical Trials Unit. Based on a legacy of mistreatment and longstanding inequities in access to health care, Black Americans, in particular, are more hesitant than other groups to embrace the use of experimental vaccines and therapies.

Debbie Lucy

In August, Ms. Lucy and her team began handing out information about the vaccine in the communities around The Mount Sinai Hospital, between 96th and 105th Streets, east of Park Avenue. In fact, Mr. Loadholt found out about the clinical trial from a friend who lives in the area and received a knock on his door from Mount Sinai.

“We have teams of people who are out in different areas trying to educate people and get them involved. We are talking to people, handing out flyers, and making as many connections as we can,” says Ms. Lucy. “We’re going to different grocery stores, hair salons, nail salons, laundromats, restaurants—any place where we think people of color are either working or going to.”

When Ms. Lucy met a man who told her that his family did not have any masks, she says she called up a team member who immediately brought several masks to the corner of East 103rd Street where they were standing. “He was in awe that we went the extra mile to do that for him,” Ms. Lucy says. “For him it was more than the masks we gave him; it was the fact that we connected with him and met his need immediately. We stood out there and talked with him and gave him additional information about participating in the trial.”

Mount Sinai has also held community forums that educate people of color about the Pfizer vaccine trial. In September, Mr. Loadholt discussed his experience at one of these forums. Ms. Lucy says, “We believe it’s easier for people who look like you to talk with you about participating in a trial because we recognize that there’s a lot of mistrust around research among people of color. Our ultimate goal is to find a vaccine that’s going to help prevent COVID-19, but with any trial we also want to test for safety to make sure it’s not causing any negative side effects in people, and that it’s well tolerated.”

Of the more than 180 COVID-19 vaccines under development, Pfizer’s RNA vaccine is one of the furthest along in the phase 3 clinical trials taking place at Mount Sinai and other locations throughout the United States. The vaccine is based on new technology and can be produced completely in vitro, or in a laboratory.

“I am grateful to individuals like Mr. Loadholt who are participating in this vaccine study and helping us to inform others,” says Judith A. Aberg, MD, the Dr. George Baehr Professor of Clinical Medicine, and Chief of Infectious Diseases for the Mount Sinai Health System. “Involvement with communities should not be overlooked due to false assumptions that people of color are unwilling to enroll in clinical trials. Such false assumptions result in harmful health disparities. We must provide everyone with the opportunity to participate in clinical trials and receive linkage to care. Only through engagement and education can people protect themselves and their loved ones.”

After receiving his second of two injections in September, Mr. Loadholt says he feels fine. He does not know whether he received the real vaccine or a placebo, which is how the placebo-controlled, randomized, observer-blinded vaccine trial is designed. He will be able to find this out in two years. “If I did receive a placebo, at least I can help another person of color receive the real one,” he says.

Mount Sinai has provided Mr. Loadholt and other trial participants with either an iPhone app or their own separate device to communicate any symptoms. “The staff at Mount Sinai has been wonderful,” Mr. Loadholt adds. “I would like Mount Sinai to do what they’re doing and be a beacon in the community.”

To potential volunteers, he says, “Don’t be afraid. Try it.”

If you are interested in volunteering for a COVID-19 vaccine clinical trial, please call 212-824-7714 or email: COVIDTRIALSINFO@MOUNTSINAI.ORG. Mount Sinai offers $119 in compensation for all visits related to the clinical trial. Watch the following video to learn more

Watch a video to learn more about our clinical trial

Mount Sinai Scientists Find Children with COVID-19-Related Illness Display a Unique Pattern of Immune Responses

Sep 28, 2020 | COVID-19, Featured, Research

In Mount Sinai’s study, the children were age 12 on average and otherwise healthy.

MIS-C is a rare, potentially life-threatening syndrome that occurs about five weeks after children have been infected by the SARS-CoV-2 virus, which causes COVID-19. Most of the children are actually asymptomatic for COVID-19, but when they develop MIS-C they are hospitalized with shock, excessive blood clotting, gastrointestinal symptoms, and heart dysfunction.

In a new development, researchers at the Icahn School of Medicine at Mount Sinai have identified a unique pattern of immune responses that characterize multisystem inflammatory syndrome in children (MIS-C) and could eventually serve as a biomarker, or reliable indicator that would help diagnose the disease.

The Mount Sinai scientists discovered this unique pattern of immune responses by using sophisticated single-cell technology to analyze the blood circulating through the bodies of nine MIS-C patients who were treated at Mount Sinai Kravis Children’s Hospital between late April and June 2020. The researchers found elevated levels of specific cytokines—molecules that regulate immunity and inflammation—and chemokines—signaling proteins—that distinguished the MIS-C patients. The children were age 12 on average, otherwise healthy, and almost equally divided between boys and girls.

“In order for us to really understand MIS-C, we had to describe the disease, and this is the first in-depth mapping of what the disease looks like,” says Dusan Bogunovic, PhD, Associate Professor of Microbiology, and Pediatrics, and Director of the Center for Inborn Errors of Immunity, part of The Mindich Child Health and Development Institute and Precision Immunology Institute. Dr. Bogunovic is the corresponding author of a Mount Sinai study that describes the findings in detail. The paper was posted to the pre-print server medRxiv.org last summer and is now published in Cell.

Dusan Bogunovic, PhD

Conor Gruber, an MD/PhD candidate at the Icahn School of Medicine, a member of the Bogunovic lab, and the paper’s first author, says, “We have mapped autoimmune parameters at an unprecedented level. Now we need to know if this autoimmune component causes the disease or is just a byproduct of MIS-C. We’re actively researching this.” Autoimmunity occurs when an individual’s antibodies mistakenly attack their body. Since the body’s adaptive immune response to disease usually forms after several weeks—the same amount of time it takes for children to develop MIS-C—the researchers believe this is likely where the problem lies within the immune system.

When the initial cases of MIS-C began surfacing in the spring, several weeks after the surge of adult COVID-19 cases in the New York metropolitan area, MIS-C was considered an atypical form of Kawasaki disease, an acute systemic inflammation of the blood vessels, mainly affecting very young children. Since then, the World Health Organization has classified MIS-C as a distinct syndrome. The Mount Sinai study found that “overlapping features are striking, suggesting that MIS-C may lie along a spectrum of Kawasaki disease-like pathology.”

Although further studies into the causes of MIS-C are needed, says Dr. Bogunovic, the good news is that widely accepted protocols are in place for the successful treatment of the disease. He is less certain, however, about whether a child’s predisposition to MIS-C portends a predisposition to different autoimmune disorders down the line or will interfere with the ability to successfully receive a COVID-19 vaccine.

“All of these postulates need careful, methodical, and well-controlled experimental dissection,” the study authors wrote. “Until then, MIS-C remains scientifically puzzling, but therapeutically manageable.”

Mount Sinai Lab Creates Shared Database to Help Scientists Find Drugs That Can Be Used to Treat COVID-19

Sep 17, 2020 | COVID-19, Featured, Research

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.”