The Albert Einstein College of Medicine dean’s office has provided funds to support new SARS-CoV-2 (COVID-19) pilot research projects by our faculty designed to generate preliminary data to support new grant applications in response to current and future SARS-CoV-2 research funding opportunities issued by the NIH and/or other funding agencies.
FUNDED PILOT PROJECTS
1. Therapeutics Development: Development of Small Molecule Inhibitors of the COVID-19 Replication Cycle
Evripidis Gavathiotis, PhD
Bogos Agianian, PhD
Adolfo Garcia-Sastre, PhD
Kris White, PhD
SARS-COV-2 is responsible for the current COVID-19 pandemic, which represents a global health emergency. There are currently no effective antiviral drugs in humans or vaccines for the virus prevention. Our proposal aims to develop a small molecule drug against the SARS-COV-2 main protease, termed Mpro or 3CL, an important drug target that is responsible for the viral replication. Our work has focused initially on repurposing existing clinical drugs while we also plan to develop novel drugs. We propose to apply our expertise in chemical and structural biology, medicinal chemistry and drug discovery to the development of COVID-19 drugs through the following specific aims: 1) Discover and design of SARS-COV-2 Mpro inhibitors using FDA-approved drugs and novel lead compounds, 2) validate and optimize SARS-COV-2 Mpro inhibitors, 3) investigate the cellular activity of SARS-COV-2 Mpro inhibitors in viral replication and infectivity assays. While our efforts will follow typical iterative drug development procedures as applied to other targets in our laboratory, based on preliminary data with a panel of FDA-approved drugs we have identified for immediate evaluation, we hope to identify drugs that may rapidly repurposed in clinical trials or require minimal optimization to address the COVID-19 health emergency.
2. Lessons from Children: Differentiating the Immune Response to COVID-19 By Age and Outcome
Betsy Herold, MD
Marla Keller, MD
The rapid spread of SARS-CoV-2 and the associated mortality highlight the urgency to identify treatment and prevention strategies. The observation that most children have relatively mild disease and rarely progress to acute respiratory disease syndrome (ARDS) provides the unique opportunity to identify protective immune responses. The hypothesis we will test is that there are quantitative and qualitative differences in the immune response to COVID-19 in children and adults that contribute to outcomes. We are uniquely positioned for these studies because of the large number of pediatric and adult cases at Montefiore and because we established a specimen biorepository linked to a clinical database and have an IRB approved protocol to obtain convalescent blood. We propose to measure serum cytokines, anti-COVID antibodies and their function (neutralizing, non-neutralizing versus enhancing) at different times to determine whether responses differs by age and outcome. We will also analyze cellular responses to viral proteins by measuring cytokine release and proliferation. We will explore mechanistic differences that contribute to the progression to ARDS and the recently described Pediatric Multisystem Inflammatory Syndrome. Results will identify what arms of the immune response should be targeted for protection and which responses need to be blocked to prevent disease progression.
3. Human and Bispecific Antibodies Against SARS-CoV2
Jonathan R. Lai, PhD (Dept. of Biochemistry)
Kartik Chandran, PhD (Dept. of Microbiology and Immunology)
The global COVID19 pandemic is caused by a novel coronavirus, SARS-CoV2, that recognizes and penetrates cells using its viral surface spike protein (S). Preliminary findings from compassionate-use studies in China utilizing convalescent plasma suggest that serum antibody can have therapeutic benefit against active infections. In this proposal, we will identify and characterize human monoclonal antibodies (mAbs) from recovered COVID19 patients that target the S protein, and then use those mAbs as templates for design of bispecific antibodies (bsAbs). Human mAbs are attractive for therapeutic and other uses because they are well-tolerated in vivo and have long half-life, owing to their human framework regions. In addition, profiling human mAb responses provides insight into immune reactions and thus can directly inform vaccine design. BsAbs provide the advantage of targeting multiple epitopes simultaneously, thus mitigating against the risk of viral escape. We obtained peripheral blood mononuclear cell (PBMC) samples from 29 convalescent patients whose sera have strong antibody reactivity toward the S protein. We will sort single B cell cells reactive toward S protein (or regions of S) at the Einstein Flow Cytometry Core, and then clone and express mAbs recombinantly. Those mAbs with favorable characteristics will be combined into bsAb designs.
4. AI Radiology to Improve Delivery of Care for COVID-19 Patients
Michael Lipton, MD, PhD
Jeffrey Levsky, MD, PhD
Parsa Mirhaji, MD, PhD
Tim Duong, PhD (collaborator at Stony Brook University)
Portable chest X-ray (CXR) has become an indispensable tool in the management of COVID-19 lung infection because it is informative and well suited for imaging contagious patients. The hallmark pathology on CXR is bilateral, peripheral hazy lung opacities progressing to air space consolidation. At admission, CXR can be the first diagnostic tool to triage patients for disease severity. While RT-PCR testing is used for primary diagnosis, there are significant limitations in assay availability and there is a known, significant false negative rate. Moreover, CXR can be used to longitudinally monitor lung disease progression, especially in a critical care setting. To date, the spatiotemporal characteristics on CXR of COVID-19 and their relationship with respect to clinical outcomes are unknown. Given shortages of ICU beds and ventilators, CXR can play a critical role in guiding clinical decision making such as hospital admission, critical care evaluation, admission to the ICU, endotracheal intubation and mechanical ventilation, timing of extubation and ICU discharge. Our overarching goal is to develop an AI algorithm to accurately stage severity, predict progression, assess treatment response, recurrence and survival, aiming to inform risk management and resource allocation associated with the COVID19 pandemic. Our immediate goals of this proposal are: a) to build a searchable imaging COVID-19 database with ground truths and clinical data, and b) to develop AI algorithms to stage disease and predict survival based on imaging and non-imaging data.
Jerry Y. Chao, MD
Investigation of Multi-system Inflammatory Syndrome in Children
We now have preliminary data in 46 children published in the Journal of Pediatrics (Chao JY, et al) demonstrating a high rate of community spread with a substantial subset of admitted pediatric patients (28.2%) requiring critical care. We seek to build on this preliminary data and analysis.
Simone Sidoli, PhD
Rapid identification of COVID-19 infection via breath screening in mass spectrometry
The objective of this proposal is to develop and optimize a new platform for rapid analysis of Exhaled Breath Condensate (EBC) of patients using mass spectrometry combined with machine learning to identify SARS-CoV2 infected patients.
Nicholas Sibinga, MD
IRF5 variants in COVID-19-associated cytokine storm with cardiovascular injury
Interferon regulatory factors (IRFs) are master regulators of innate immune signaling. Specific Aim: Evaluate the peripheral blood transcriptome of COVID-19 patients with compromised cardiovascular function, with a focus on interferon regulatory factor (IRF)-5 variants and relevant microRNAs.