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March 19th, 2020

Gilead Sciences Updates (2-26) Company’s Ongoing Response to COVID-19 with Investigational Compound Remdesivir

In a February 26, 2020 report, Gilead Sciences said that it is working closely with global health authorities to respond to the novel coronavirus (COVID-19) outbreak through the appropriate experimental use of the investigational compound remdesivir ( (image). Together with the U.S. Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), Department of Health and Human Services (DHHS), National Institute of Allergies and Infectious Diseases (NIAID) and Department of Defense (DoD) - CBRN Medical; the China CDC and National Medical Product Administration (NMPA); the World Health Organization (WHO); and individual researchers and clinicians; Gilead is focused on contributing its antiviral expertise and resources to help patients and communities fighting COVID-19. Remdesivir is an investigational nucleotide analog with broad-spectrum antiviral activity – it is not approved anywhere globally for any use. Remdesivir has demonstrated in vitro and in vivo activity in animal models against the viral pathogens MERS and SARS, which are also coronaviruses and are structurally similar to COVID-19. The limited preclinical data on remdesivir in MERS and SARS indicate that remdesivir may have potential activity against COVID-19. This is an experimental medicine that has only been used in a small number of patients with COVID-19 to date, so Gilead does not have an appropriately robust understanding of the effect of this drug to warrant broad use at this time. Gilead’s response to COVID-19 entails three main areas. The first is clinical trials. Gilead-Initiated Trials: Gilead has initiated two Phase 3 clinical studies to evaluate the safety and efficacy of remdesivir in adults diagnosed with COVID-19 following the U.S.

March 18th

Capricor Therapeutics Announces Strategic Plan for Product Expansion of Its Exosome Platform Technologies; Company Appoints Exosome Expert Dr. Stephen Gould from Hopkins As Executive Consultant

On March 17, 2020, Capricor Therapeutics (NASDAQ: CAPR), a clinical-stage biotechnology company focused on the development of first-in-class biological therapeutics for the treatment of Duchenne muscular dystrophy (DMD) and other rare disorders, announced the expansion of its strategic plan to further develop the company’s exosome platform technologies. In conjunction with these efforts, Stephen J. Gould (photo), PhD. has been appointed as Executive Consultant to guide Capricor’s development of exosome-based vaccines and exosome-based therapeutics. Dr. Gould, a Professor of Biological Chemistry at Johns Hopkins University, is an internationally recognized exosome expert who brings an unparalleled understanding of exosome engineering to Capricor’s exosome-based research and development programs. “One of the reasons the exosomes are potentially so useful and transformative is their ability to speak the language of a cell. We are excited by the commitment of Dr. Gould to help us explore the potential of exosome-based vaccines to help prevent human diseases and exosome-based therapeutics in treating human diseases. We look forward to announcing more updates shortly which will further outline some of our near-term goals within our exosomes program,” said Linda Marbán, PhD, Capricor’s President and Chief Executive Officer. Dr. Gould stated, “Exosomes are the body’s natural way of sending complex signals between cells and tissues. As a result, exosome-based vaccines have the potential to elicit more effective immune reactions against infectious agents and cancers, while exosome-based therapeutics have the potential to stabilize drugs and deliver them to their intended site of action.

Chemists Reveal Structure & Detailed Function of Bacterial Enzyme That Breaks Down Collagen; Enzyme Enables Unique Chemistry & Could Become New Target for Antibiotics to Treat C. difficile Infections

MIT and Harvard University chemists have discovered the structure of an unusual bacterial enzyme that can break down an amino acid found in collagen, which is the most abundant protein in the human body. The enzyme, known as hydroxy-L-proline dehydratase (HypD), has been found in a few hundred species of bacteria that live in the human gut, including Clostridioides difficile. The enzyme performs a novel chemical reaction that dismantles hydroxy-L-proline, the molecule that gives collagen its tough, triple-helix structure. Now that researchers know the structure of the enzyme, they can try to develop drugs that inhibit it. Such a drug could be useful in treating C. difficile infections, which are resistant to many existing antibiotics. "This is very exciting because this enzyme doesn't exist in humans, so it could be a potential target," says Catherine Drennan, PhD, an MIT Professor of Chemistry and Biology and a Howard Hughes Medical Institute Investigator. "If you could potentially inhibit that enzyme, that could be a unique antibiotic." Dr. Drennan and Emily Balskus, PhD, a Professor of Chemistry and Chemical Biology at Harvard University, are the senior authors of the study, which was published online on March 17, 2020 in eLife. The open-access article is titled "Molecular Basis for Catabolism of the Abundant Metabolite Trans-4-Hydroxy-L-Proline by a Microbial Glycyl Radical Enzyme." MIT graduate student Lindsey Backman and former Harvard graduate student Yolanda Huang, PhD, are the lead authors of the study. The HypD enzyme is a member of a large family of proteins called glycyl radical enzymes. These enzymes work in an unusual way, by converting a molecule of glycine, the simplest amino acid, into a radical -- a molecule that has one unpaired electron.

March 17th

Regeneron Announces Important Advances in Novel COVID-19 Antibody Program; Human Clinical Studies of Virus-Neutralizing Anti-Spike Protein Antibody Cocktail Anticipated by Summer

On March 17, 2020, Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced the latest progress in its efforts to discover and develop a novel multi-antibody cocktail that can be administered as prophylaxis before exposure to the SARS-CoV-2 virus or as treatment for those already infected. Regeneron scientists have now isolated hundreds of virus-neutralizing, fully human antibodies from the company's VelocImmune® mice, which have been genetically-modified to have a human immune system. Regeneron has also isolated antibodies from humans who have recovered from COVID-19, in order to maximize the pool of potentially potent antibodies. From this large pool of candidates, Regeneron will select the top two antibodies for a “cocktail” treatment based on potency and binding ability to the SARS-CoV-2 spike protein, as well as other desirable qualities. Using a multi-antibody approach allows for targeting of different parts of the virus and may help protect against multiple viral variants. Regeneron previously used these technologies to rapidly develop a successful treatment for Ebola virus infection, which is currently under review by the U.S. Food and Drug Administration. In order to meet the pressing public health need, Regeneron is applying its VelociMab® technology to prepare manufacturing-ready cell lines as lead antibodies are selected, so that clinical-scale production can begin immediately. The company is working toward the goal of producing hundreds of thousands of prophylactic doses per month by the end of summer and hopes to have smaller quantities available for initial clinical testing at the beginning of the summer. The company is working with the U.S. Health & Human Services' Biomedical Advanced Research and Defense Authority (BARDA) to increase capacity even further.

New Understanding of Flexible Structure of Interleukin-2 (IL-2) May Guide Drug Discovery

The signaling molecule interleukin-2 (IL-2) has long been known to have powerful effects on the immune system, but efforts to harness it for therapeutic purposes have been hampered by serious side effects. Now researchers have worked out the details of IL-2's complex interactions with receptor molecules on immune cells, providing a blueprint for the development of more targeted therapies for treating cancer or autoimmune diseases. IL-2 acts as a growth factor to stimulate the expansion of T cell populations during an immune response. Different types of T cells play different roles, and IL-2 can stimulate both effector T cells, which lead the immune system's attack on specific antigens, and regulatory T cells, which serve to rein in the immune system after the threat is gone. "IL-2 can act as either a throttle or a brake on the immune response in different contexts," said Nikolaos Sgourakis, PhD, Assistant Professor of Chemistry and Biochemistry at the University of California (UC), Santa Cruz. "Our investigation used detailed biophysical methods to show how it does this." Dr. Sgourakis is a corresponding author of the new study, published online on March 17, 2020 in PNAS. The article is titled “Interleukin-2 Druggability Is Modulated by Global Conformational Transitions Controlled by a Helical Capping Switch.” The first author, Viviane De Paula, PhD, a visiting scientist in his lab from the Federal University of Rio de Janeiro, used nuclear magnetic resonance spectroscopy (NMR) to observe IL-2's structural dynamics. The study was done in close collaboration with corresponding author Dr. Christopher Garcia's group at Stanford University. The researchers were able to show that IL-2 adopts two different structural forms (termed conformations) that affect how it interacts with the receptors on different types of T cells.

Melbourne Researchers Map Immune Responses from One of Australia's First Coronavirus (COVID-19) Patients, Showing the Body's Ability to Fight the Virus and Recover from the Infection

Melbourne researchers have mapped immune responses from one of Australia's first novel coronavirus (COVID-19) patients, showing the body's ability to fight the virus and recover from the infection. Researchers at the Peter Doherty Institute for Infection and Immunity (Doherty Institute) - a joint venture between the University of Melbourne and the Royal Melbourne hospital - were able to test blood samples at four different time points in an otherwise healthy woman in her 40s, who presented with COVID-19 and had mild-to-moderate symptoms requiring hospital admission. Published online on March 16, 2020 in Nature Medicine is a detailed report of how the patient's immune system responded to the virus. The open-access article is titled “Breadth of Concomitant Immune Responses Prior to Patient Recovery: A Case Report of Non-Severe COVID-19.” One of the authors on the paper, research fellow Dr. Oanh Nguyen, said this was the first time that broad immune responses to COVID-19 have been reported. "We looked at the whole breadth of the immune response in this patient using the knowledge we have built over many years of looking at immune responses in patients hospitalized with influenza," Dr. Nguyen said. "Three days after the patient was admitted, we saw large populations of several immune cells, which are often a tell-tale sign of recovery during seasonal influenza infection, so we predicted that the patient would recover in three days, which is what happened." The research team was able to do this research so rapidly thanks to the SETREP-ID (Sentinel Travelers and Research Preparedness for Emerging Infectious Disease) platform, led by Royal Melbourne Hospital Infectious Diseases Physician Dr. Irani Thevarajan at the Doherty Institute.

March 16th

NIH Clinical Trial of Investigational Vaccine for COVID-19 Begins; Vaccine Is mRNA Coding for Viral Spike Protein; Vaccine Developed by Collaborating Scientists at Moderna and NIAID

A Phase 1 clinical trial evaluating an investigational vaccine designed to protect against coronavirus disease 2019 (COVID-19) has begun at Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is funding the trial. KPWHRI is part of NIAID’s Infectious Diseases Clinical Research Consortium. The open-label trial will enroll 45 Seattle-based healthy adult volunteers ages 18 to 55 years over approximately 6 weeks. The first participant received the investigational vaccine today (March 16, 2020). The study is evaluating different doses of the experimental vaccine for safety and its ability to induce an immune response in participants. This is the first of multiple steps in the clinical trial process for evaluating the potential benefit of the vaccine. The vaccine is called mRNA-1273 (a messenger RNA molecule that codes for a COVID-19 spike protein) and was developed by NIAID scientists and their collaborators at the biotechnology company Moderna, Inc., based in Cambridge, Massachusetts. The Coalition for Epidemic Preparedness Innovations (CEPI) supported the manufacturing of the vaccine candidate for the Phase 1 clinical trial. “Finding a safe and effective vaccine to prevent infection with SARS-CoV-2 is an urgent public health priority,” said NIAID Director Anthony S. Fauci, MD. “This Phase 1 study, launched in record speed, is an important first step toward achieving that goal.” Infection with SARS-CoV-2, the virus that causes COVID-19, can cause a mild to severe respiratory illness and include symptoms of fever, cough, and shortness of breath.

Hopkins/Einstein Experts Recommend Using Antibodies from COVID-19 Survivors As Stopgap Measure to Treat Patients and Protect Healthcare Workers; Approach Has Seen Success in Deadly Pathogen Outbreaks for 100 Years

Countries fighting outbreaks of the novel coronavirus disease COVID-19 should consider using the antibodies of people who have recovered from infection to treat cases and provide short-term immunity—lasting weeks to months—to critical health care workers, argue two infectious disease experts--Arturo Casadevall, MD, PhD, Professor and Chair of the Department of the Molecular Microbiology and Immunology at The Johns Hopkins Bloomberg School of Public Health in Baltimore. and Liise-anne Pirofski, MD, Chief of the Division of Infectious Diseases at the Albert Einstein College of Medicine in New York City. In an open-access essay published online on March 13, 2020 in The Journal of Clinical Investigation ( Dr. Casadevall and Dr. Pirofski, wrote that the infusion of antibody-containing serum from convalescing patients has a long history of effective use as a stopgap measure against infectious diseases, and can be implemented relatively quickly—long before other antiviral treatments, monoclonal antibodies, and vaccines are developed, approved, and available. The JCI essay is titled “The Convalescent Sera Option for Containing COVID-19.” “In addition to public health containment and mitigation protocols, this may be our only near-term option for treating and preventing COVID-19, and it is something we can start putting into place in the next few weeks and months,” Dr. Casadevall says. To date, the novel coronavirus SARS-CoV-2 that appears to have originated in Wuhan, China, in late 2019 has caused outbreaks of COVID-19 across the world.

March 13th

Newly Discovered Family of Flexible, Heat-Resistant, Non-Chaperone Proteins Protect Against Protein Instability and Aggregation; The Newly Identified “Hero” Proteins May Find Application in Neurodegenerative Diseases

Protein aggregation and misfolding underpin several neurodegenerative diseases such as Huntington’s and Alzheimer’s. Proteins can also become aggregated or denatured under conditions of stress, such as extreme heat. A new study, published online on March 12, 2020 in the open-access journal PLOS Biology by Dr. Kotaro Tsuboyama and Dr. Yukihide Tomari (photo) of The University of Tokyo, Japan, and colleagues, reveals a newly discovered family of proteins in both humans and flies which protect vulnerable proteins from becoming aggregated or denatured in extreme heat and other stresses – a function previously only known in “extremophile” organisms such as heat-loving bacteria. The PLOS Biology article is titled “A Widespread Family of Heat-Resistant Obscure (Hero) Proteins Protect Against Protein Instability and Aggregation.” The proteins, discovered through a serendipitous observation, may find applications in biotechnology and protection from neurodegenerative disease. Proteins are molecules held in their active folded shape by weak attractions between and among amino acids. Heat can disrupt these attractions, changing protein shape and causing them to clump together. This also stops the proteins from functioning. An entire class of already known proteins—the “molecular chaperones”—use cellular energy in the form of ATP to either refold or dispose of misfolded proteins. But for proteins in most organisms, temperatures close to the boiling point of water irreversibly destroy their structure. In the course of their research on an entirely different question, while trying to purify a structurally unstable fly protein called Ago2, the authors of the PLOS Biology article found that liquid extracted by breaking open fly cells contained some factor that stabilized this Ago2 protein.

March 11th

New Study Sheds Light on “Dark Region” of Drosophila Genome

Just as there is a mysterious dark matter that accounts for 85 percent of our universe, there is a "dark" portion of the human genome that has perplexed scientists for decades. A study published online on March 6, 2020, in Genome Research identifies new portions of the fruit fly genome that, until now, have been hidden in these dark, silent areas. The collaborative open-access paper, titled "Gene Expression Networks in the Drosophila Genetic Reference Panel," is the culmination of years of research by Clemson University geneticists Trudy Mackay, PhD, and Robert Anholt, PhD. Their ground-breaking findings could significantly advance science's understanding of a number of genetic disorders. The "dark" portion refers to the approximate 98 percent of the genome that doesn't appear to have any obvious function. Only 2 percent of the human genome codes for proteins, the building blocks of our bodies and the catalysts of the chemical reactions that allow us to thrive. Scientists have been puzzled by this since the 1970s when gene sequencing technologies were first developed, revealing the proportion of coding to noncoding regions of the genome. Genes are traditionally thought to be transcribed into RNAs, which are subsequently translated into proteins, as dictated by the central dogma of molecular biology. However, the entire assemblage of RNA transcripts in the genome, called the “transcriptome,” contains RNA species that appear to have some other function, apart from coding for proteins. Some scientists have proposed that noncoding regions might contain regulatory regions that control gene expression and the structure of chromosomes, yet these hypotheses were difficult to study in past years as diagnostic technology was developing.