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April 17th, 2020

Researchers Move Closer to Producing Heparin Anti-Coagulant in the Lab; UC San Diego Group Demonstrates Influence of Transcription Factor ZNF263 on Heparin Synthesis

In a recent study published online on April 10, 2020in the Proceedings of the National Academy of Sciences (PNAS), University of California (UC) San Diego researchers moved one step closer to the ability to make heparin (image) of structure) in cultured cells. The article is titled “ZNF263 Is a Transcriptional Regulator of Heparin and Heparan Sulfate Biosynthesis.” Heparin is a potent anti-coagulant and the most prescribed drug in hospitals, yet cell-culture-based production of heparin is currently not possible. In particular, the researchers found a critical gene in heparin biosynthesis: ZNF263 (zinc-finger protein 263). The researchers believe this gene regulator is a key discovery on the way to industrial heparin production. The idea would be to control this regulator in industrial cell lines using genetic engineering, paving the way for safe industrial production of heparin in well-controlled cell culture. Heparin is currently produced by extracting the drug from pig intestines, which is a concern for safety, sustainability, and security reasons. Millions of pigs are needed each year to meet our needs, and most manufacturing is done outside the USA. Furthermore, ten years ago, contaminants from the pig preparations led to dozens of deaths. Thus, there is a need to develop sustainable recombinant production. The work in PNAS provides new insights on exactly how cells control synthesis of heparin. Heparin is a special subtype of a more general class of carbohydrates, called heparan sulfates, that are produced by a wide range of cells, both in the human body, as well as in cell culture. Yet, heparin is exclusively produced in a special type of blood cells called mast cells. To this day, heparin cannot be successfully produced in cell culture.

New Ebola Vaccine May Fight All Four Ebola Virus Species That Infect Humans

Infectious disease scientists report early development of a potential universal vaccine for Ebola viruses that preclinical tests show might neutralize all four species of these deadly viruses infecting people in recent outbreaks, mainly in Africa. Scientists at Cincinnati Children's Hospital Medical Center report their preclinical results in an article published online on February 19, 2020 in the Journal of Virology, published by the American Society for Microbiology. The article is titled “A Bivalent, Spherical Virus-Like Particle Vaccine Enhances Breadth of Immune Responses Against Pathogenic Ebola Viruses in Rhesus Macaques.” Although still in early preclinical testing, the researchers report that their data indicate that the prospective vaccine has potential to be a stand-alone protection from Ebola. It also could broaden and extend the durability of protective immunity induced by current live vaccines already being tested in clinical trials against individual Ebola virus species, said Karnail Singh, PhD, the study's co-principal investigator in the Division of Infectious Diseases at Cincinnati Children’s. "This could be a significant advancement in the global effort to prevent or manage Ebola outbreaks, especially if this vaccine, used alone or in combination with another Ebola vaccine, results in long-term and durable protective immunity against different Ebola viruses," Dr. Singh said. A deadly Ebola outbreak in West Africa between 2013 and 2016 accelerated international efforts to develop vaccines for these highly infectious and harmful viruses. This led to development of recombinant Ebola vaccines in which glycoprotein from Zaire Ebola virus is engineered into another modified live viral vector.

April 11th

Trial Drug (Soluble Form of ACE2) Can Significantly Impact Early Stages of COVID-19 Infection in Engineered Human Tissues; Drug Interferes with Viral Spike Binding to ACE2 Receptor on Cell Surfaces

An international team led by University of British Columbia (UBC) researcher Dr. Josef Penninger has found a trial drug that effectively blocks the cellular door SARS-CoV-2 uses to infect its hosts. The findings, published online on April 2, 2020 in Cell, hold promise as a treatment capable of stopping early infection of the novel coronavirus that, as of April 2, 2020, had affected more than 981,000 people and claimed the lives of 50,000 people worldwide. The study provides new insights into key aspects of SARS-CoV-2, the virus that causes COVID-19, and its interactions on a cellular level, as well as how the virus can infect blood vessels and kidneys. The open-access article is titled "Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2." We are hopeful our results have implications for the development of a novel drug for the treatment of this unprecedented pandemic," says Dr. Penninger, Professor in UBC's Faculty of Medicine, Director of the Life Sciences Institute and the Canada 150 Research Chair in Functional Genetics at UBC. "This work stems from an amazing collaboration among academic researchers and companies, including Dr. Ryan Conder's gastrointestinal group at STEMCELL Technologies in Vancouver; Nuria Montserrat in Spain; Drs. Haibo Zhang and Art Slutsky from Toronto; and especially Ali Mirazimi's infectious biology team in Sweden, who have been working tirelessly day and night for weeks to better understand the pathology of this disease and to provide breakthrough therapeutic options." ACE2 (angiotensin-converting enzyme 2)-- a protein on the surface of the cell membrane -- is now at center-stage in this outbreak as the key receptor for the spike glycoprotein of SARS-CoV-2. In earlier work, Dr.

March 22nd

FDA Approves 45-Minute Point-of-Care COVID-19 Test; First Rapid, Near-Patient Molecular Test for Detection of Virus that Causes COVID-19 Developed by California’s Cepheid

On March 21, 2020, California-based Cepheid announced that it has received Emergency Use Authorization (EUA) from the FDA for its Xpert® Xpress SARS-CoV-2, a rapid molecular diagnostic test for qualitative detection of SARS-CoV-2, the virus causing COVID-19. The test has been designed to operate on any of Cepheid's more than 23,000 automated GeneXpert® Systems worldwide, with a detection time of approximately 45 minutes with less than a minute of hands on time to prepare the sample. "During this time of increased demand for hospital services, Clinicians urgently need an on-demand diagnostic test for real-time management of patients being evaluated for admission to health-care facilities. An accurate test delivered close to the patient can be transformative — and help alleviate the pressure that the emergence of the 2019-nCoV outbreak has put on healthcare facilities that need to properly allocate their respiratory isolation resources," said Dr. David Persing, MD, PhD, Chief Medical and Technology Officer at Cepheid. "By leveraging the design principles of our current Xpert Xpress Flu/RSV cartridge technology, in which multiple regions of the viral genome are targeted to provide rapid detection of current and potential future variants of SARS-CoV-2, we have developed a test that provides reference lab-quality results in multiple settings where actionable treatment information is needed quickly." "Cepheid currently has nearly 5,000 GeneXpert® Systems in the US capable of point-of-care testing and for use in hospitals," said Cepheid President Warren Kocmond.

March 19th

NIH Clinical Trial of Gilead's Remdesivir to Treat COVID-19 Begun in Nebraska

In a February 25, 2020 press release, the FDA announced that a randomized, controlled clinical trial to evaluate the safety and efficacy of the investigational antiviral remdesivir in hospitalized adults diagnosed with coronavirus disease 2019 (COVID-19) has begun at the University of Nebraska Medical Center (UNMC) in Omaha. The trial regulatory sponsor is the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. This is the first clinical trial in the United States to evaluate an experimental treatment for COVID-19, the respiratory disease first detected in December 2019 in Wuhan, Hubei Province, China. The first trial participant is an American who was repatriated after being quarantined on the Diamond Princess cruise ship that docked in Yokohama, Japan and volunteered to participate in the study. The study can be adapted to evaluate additional investigative treatments and to enroll participants at other sites in the U.S. and worldwide. There are no specific therapeutics approved by the Food and Drug Administration (FDA) to treat people with COVID-19, the disease caused by the newly emergent SARS-CoV-2 virus (formerly known as 2019-nCoV). Infection can cause mild to severe respiratory illness, and symptoms can include fever, cough, and shortness of breath. As of February 24, the World Health Organization (WHO) had reported 77,262 confirmed cases of COVID-19 and 2,595 deaths in China and 2,069 cases of COVID-19 and 23 deaths in 29 other countries. There had been 14 confirmed COVID-19 cases reported in the United States and an additional 39 cases among persons repatriated to the United States, according to the Centers for Disease Control and Prevention (CDC) at that time.

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 (https://en.wikipedia.org/wiki/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.