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RNA Is Key in Helping Stem Cells Know What to Become; Polycomb Repressive Complex 2 (PRC2) Requires RNA Binding for Chromatin Localization in Human Pluripotent Stem Cells and for Defining Cellular State, Paper from Nobelist Cech & Rinn Labs Asserts

Look deep inside our cells, and you'll find that each has an identical genome--a complete set of genes that provides the instructions for our cells' form and function. But if each blueprint is identical, why does an eye cell look and act differently than a skin cell or a brain cell? How does a stem cell--the raw material with which our organ and tissue cells are made--know what to become? In a study published online on July 6, 2020 in Nature Genetics (, University of Colorado-Boulder (CU Boulder) researchers come one step closer to answering that fundamental question, concluding that the molecular messenger RNA (ribonucleic acid) plays an indispensable role in cell differentiation, serving as a bridge between our genes and the so-called "epigenetic" machinery that turns them on and off. When that bridge is missing or flawed, the researchers report in their article, a stem cell on the path to becoming a heart cell never learns how to beat. The article is titled “RNA Is Essential for PRC2 Chromatin Occupancy and Function in Human Pluripotent Stem Cells.” The paper comes at a time when pharmaceutical companies are taking unprecedented interest in RNA. And, while the research is young, it could ultimately inform development of new RNA-targeted therapies, from cancer treatments to therapies for cardiac abnormalities. "All genes are not expressed all the time in all cells. Instead, each tissue type has its own epigenetic program that determines which genes get turned on or off at any moment," said co-senior author Thomas Cech (photo) (, PhD, a Nobel laureate and Distinguished Professor of Biochemistry. "We determined in great detail that RNA is a master regulator of this epigenetic silencing and that in the absence of RNA, this system cannot work. It is critical for life."

Experimental Drug (Tofersen from Biogen) Shows Early Promise Against Rare Inherited Form of ALS Caused by Mutations in Superoxide Dismutase 1 (SOD1)

An experimental drug for a rare, inherited form of amyotrophic lateral sclerosis (ALS) (Lou Gehrig’s disease) has shown promise in a phase 1/phase 2 clinical trial conducted at Washington University School of Medicine in St. Louis, Massachusetts General Hospital in Boston, and other sites around the world and sponsored by the pharmaceutical company Biogen Inc. The trial indicated that the experimental drug, known as tofersen, shows evidence of safety that warrants further investigation and lowers levels of a disease-causing protein in people with a type of amyotrophic lateral sclerosis, or ALS, caused by mutations in the gene SOD1 (superoxide dismutase 1). The results of the study, published on July 9, 2020 in the New England Journal of Medicine (, have led to the launch of a phase 3 clinical trial to further evaluate the safety and efficacy of tofersen, The NEJM article is titled "Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS." "ALS is a devastating, incurable illness," said principal investigator Timothy M. Miller (Photo, Credit: Huy Mach), MD, PhD, the David Clayson Professor of Neurology at Washington University and Director of the ALS Center at the School of Medicine. "While this investigational drug is aimed at only a small percentage of people with ALS, the same approach--blocking the production of specific proteins at the root of the illness--may help people with other forms of the illness. "This trial indicated that tofersen shows evidence of safety that warrants further investigation and that the dose we used lowers clinical markers of disease. There are even some signs that it slowed clinical progression of ALS, although the study was not designed to evaluate effectiveness at treating the disease, so we can't say anything definitive.

Hormone (GDF15) Being Studied As Possible Treatment for Obesity Is Risk Factor for Sepsis, New Study Shows; Inhibitor of GDF15 May Be Useful As Complementary Treatment for Sepsis

A group of scientists from the Instituto Gulbenkian de Ciência (IGC) ( in Portugal, led by Luís Moita, PhD, discovered that a hormone that is being studied as a treatment for obesity reduces the resistance to infection caused by bacteria and is a risk factor for sepsis. The work, developed in collaboration among researchers from Portugal, France, Germany, and South Korea, was published online on June 2, 2020 in PNAS. The open-access article is titled “CXCL5-Mediated Recruitment of Neutrophils into the Peritoneal Cavity of Gdf15-Deficient Mice Protects Against Abdominal Sepsis” ( Sepsis is a potentially fatal illness, that derives from a deregulated response of the organism to an infection, leading to organ malfunction. A study recently published in the scientific journal The Lancet (, estimated that, in 2017, sepsis affected 49 million people and 11 million people worldwide have died. With the aim of expanding knowledge about this disease, Dr. Moita’s team at IGC investigated whether the hormone known as GDF15 (growth and differentiation factor 15) could play a role in sepsis. This hormone is currently being widely studied by several laboratories and pharmaceutical companies as a treatment for obesity. “We’ve discovered a critical effect of GDF15 on infection, which is relevant because this hormone increases in many common diseases, like obesity, [and] pulmonary and cardiovascular diseases”, explains Dr. Moita.

Under Oxidative Stress from Hydrogen Peroxide (H2O2), Defensive Clp Proteins of E. coli Ensure That Iron Pools Remain Sufficient for Reactivation of Key Oxidized Metalloenzymes

Researchers at the University of Illinois, Urbana-Champaign, have shown that, during oxidative stress from hydrogen peroxide (H2O2), Clp proteins in E. coli act to ensure that cellular pools of iron remain adequate and accessible for the reactivation of oxidized metalloenzymes. This system countervails the simultaneous drive to sequester iron, which can react with H2O2 and cause DNA damage. The researchers concluded that E. coli cells are able to strike a careful balance, diminishing iron pools enough to protect the cell’s DNA (from hydroxyl radicals that are produced when iron reacts with H2O2), but keeping the iron pools substantial enough so that critical iron-dependent enzymes can be repaired. The results were published online on June 29, 2020 in the Journal of Bacteriology. The article is titled “During Oxidative Stress the Clp Proteins of Escherichia coli Ensure That Iron Pools Remain Sufficient to Reactivate Oxidized Metalloenzymes.” The authors are first author Ananya Sen (photo), Yidan Zhou, and Professor James A. Imlay, from the Department of Microbiology at the University of Illinois, Urbana-Champaign. The authors noted that “H2O2 is formed in natural environments by both biotic and abiotic processes. It easily enters the cytoplasms of microorganisms, where it can disrupt growth by inactivating iron-dependent enzymes. It also reacts with the intracellular iron pool, generating hydroxyl radicals that can lethally damage DNA.” Consequently, the authors said that bacteria have developed various mechanisms to combat the potential damage that can be caused by H2O2. Bacteria possess H2O2-responsive transcription factors that control defensive regulons (sets of related genes that are activated together). These defensive regulons typically code for catalases and peroxidases that scavenge H2O2.

CytoDyn’s Leronlimab Prevents Transmission of SHIV in Macaque Study; Results of Preclinical Study Presented Tuesday, July 7, in Oral Presentation at the 23rd International AIDS Conference (AIDS 2020)

On July 7, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with potential clinical indications for HIV, COVID-19, cancer, GvHD (graft versus host disease), and NASH (non-alcoholic steato-hepatitis), announced the results from a preclinical macaque study evaluating leronlimab as pre-exposure prophylaxis (PrEP) to prevent sexual HIV transmission. The study evaluated the impact of a macaque-equivalent dose of either 350 mg (once weekly) or 700 mg (bi-monthly) leronlimab on acquisition of infection in a total of 18 animals, and found that the equivalent 700 mg bi-monthly leronlimab dose completely prevented rectal transmission of Simian-Human Immunodeficiency Virus (SHIV) in macaques. These results were presented today in an oral presentation titled “CCR5 Antibody Blockade Protects Rhesus Macaques from Rectal SHIV Acquisition" at the 23rd International AIDS Conference (AIDS 2020) ( “The results reported here in the preclinical macaque model of HIV sexual transmission support leronlimab as a possible PrEP (pre-exposure prophylaxis) agent at a time when long-acting human HIV PrEP options are limited,” said Jonah Sacha, PhD, Professor at Oregon Health & Science University (OHSU), and the study’s lead investigator. “We are eager to build upon these preclinical results describing leronlimab’s utility in HIV prevention by initiating clinical studies for leronlimab as a PrEP treatment. Current PrEP options require a continued daily dosing regimen in order to be effective and are inherently difficult to maintain in the long-term,” said Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn, which has developed leronlimab.

Novavax Announces $1.6 Billion Funding from Operation Warp Speed to Support Late-Stage Clinical Development, Pivotal Phase 3 Clinical Trial to Support Licensure, Large-Scale Manufacturing & Production of 100 Million Vaccine Doses Starting in Late 2020

On June 7, 2020, Novavax, Inc. (Nasdaq: NVAX) (, a late-stage biotechnology company developing next-generation vaccines for serious infectious diseases, announced that it has been selected to participate in Operation Warp Speed (OWS), a U.S. government program that aims to begin delivering millions of doses of a safe, effective vaccine for COVID-19 in 2021. Novavax has been awarded $1.6 billion by the federal government to complete late-stage clinical development, including a pivotal Phase 3 clinical trial; establish large-scale manufacturing; and deliver 100 million doses of NVX CoV2373, Novavax’ COVID-19 vaccine candidate, as early as late 2020. NVX CoV2373 consists of a stable, prefusion protein made using its proprietary nanoparticle technology and includes Novavax’ proprietary Matrix M™ adjuvant. “The pandemic has caused an unprecedented public health crisis, making it more important than ever that industry, government, and funding entities join forces to defeat the novel coronavirus together. We are honored to partner with Operation Warp Speed to move our vaccine candidate forward with extraordinary urgency in the quest to provide vital protection to our nation’s population,” said Stanley C. Erck, MBA, President and Chief Executive Officer of Novavax. “We are grateful to the U.S. government for its confidence in our technology platform, and are working tirelessly to develop and produce a vaccine for this global health crisis.” Under terms of the agreement, Novavax will demonstrate it can rapidly stand up large-scale manufacturing and transition into ongoing production, including the capability to stockpile and distribute large quantities of NVX-CoV2373 when needed.

Exosomes from MSCs Should Be Used in Place of MSCs Themselves for Treatment of “Cytokine Storm” and Severe Pneumonia in COVID-19, Yale Expert Argues; Also, Presence & Role(s) of Billions of Exosomes in Convalescent Plasma Need to Be Considered

In an “Urgent Opinion” pre-print ( posted online on July 1, 2020, Philip Askenase ( (, MD, Professor of Medicine (Clinical Immunology) at the Yale University School of Medicine in the Section of Rheumatology and Clinical Immunology, and former Chief of Allergy & Clinical Immunology at the Yale University School of Medicine, argues that exosomes released from mesenchymal stromal cells (MSCs), should be used instead of MSCs for treatment of the profound clinical “cytokine storm” and severe pneumonia that can occur in COVID-19. He also contends that the presence and role of the billions of exosomes present in convalescent plasma should be considered when using this treatment approach. With regard to the MSC exosomes, Dr. Askenase notes that, although MSCs are increasingly used in the treatment of cytokine storms and pneumonia in COVID-19, many reports in the literature have shown “definitively” that the release of exosomes from in vivo administered MSCs is actually responsible for the beneficial effects associated with the MSCs. In addition, Dr. Askenase noted that exosomes are superior, simpler, and clinically more convenient when compared to their parental MSCs. Furthermore, he pointed out that, in the context of COVID-19, the known tendency of MSCs to aggregate and to cause lung dysfunction might combine with the COVID-19 pneumonia tendencies to exacerbate, rather than help, lung problems associated with COVID-19. In addition, he suggested that the tendency of MSCs to form peripheral vascular micro-aggregates, might synergize with the vascular clots associated with COVID-19 to cause significant central and/or peripheral vascular insufficiency.

Article Examines Epigenetics in Developing Mammalian Embryo; H3K9me3 Histone Marker, Normally Repressive of Gene Expression, Is Non-Repressive in Embryo; Possible New Clue to Cell Reprogramming

Maria-Elena Torres-Padilla (photo), PhD, Director of the Institute of Epigenetics and Stem Cells at Helmholtz Zentrum München, and her colleague Adam Burton, PhD, are doing pioneering work in the field of epigenetics. Together with colleagues, Dr. Torres-Padilla and Dr. Burton published an article on epigenetics in the embryo online on June 29, 2020 in Nature Cell Biology. The article is titled “Heterochromatin Establishment During Early Mammalian Development Is Regulated by Pericentromeric RNA and Characterized By Non-Repressive H3k9me3.” Below, Dr. Torres-Padilla and Dr. Burton responded to some questions on their work. The first question was “Why would we want to reprogram cells?” Dr. Padilla-Lopez answered by saying, “Can you imagine being able to artificially generate cells that can develop into any cell type? That would be really fantastic! We call this ability 'totipotency' and it is the highest level of cellular plasticity. When you think about using healthy cells to replace sick cells, for example in regeneration and replacement therapies, you need to think about how to generate those 'new' healthy cells. For that, you often need to 'reprogram' other cells, that means, to be able to change one cell into the cell type of interest. In nature, cellular reprogramming happens in the early embryo at fertilization. It is a purely epigenetic process since the DNA content of the embryo's cells does not change, only the genes they express. Epigenetics mediates changes in gene expression meaning the way our genes are 'read' from our genetic makeup, which is largely imposed by chromatin.

Regeneron Announces Start of REGN-COV2 Phase 3 COVID-19 Prevention Trial in Collaboration with NIAID; Anti-Viral Antibody Cocktail REGN-COV2 Is Also in Phase 2/3 Treatment Trials Following Positive Phase 1 Safety Review

On July 6, 2020, Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced the initiation of late-stage clinical trials evaluating REGN-COV2, Regeneron's investigational double antibody cocktail for the treatment and prevention of COVID-19. A Phase 3 trial will evaluate REGN-COV2's ability to prevent infection among uninfected people who have had close exposure to a COVID-19 patient (such as the patient's housemate), and is being run jointly with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). REGN-COV2 has also moved into the Phase 2/3 portion of two adaptive Phase 1/2/3 trials testing the cocktail's ability to treat hospitalized and non-hospitalized (or "ambulatory") patients with COVID-19. This clinical progress follows a positive review from the Independent Data Monitoring Committee of REGN-COV2 Phase 1 safety results in an initial cohort of 30 hospitalized and non-hospitalized patients with COVID-19. The Phase 3 prevention trial is being conducted at approximately 100 sites and is expected to enroll 2,000 patients in the U.S.; the trial will assess SARS-CoV-2 infection status. The two Phase 2/3 treatment trials in hospitalized (estimated enrollment =1,850) and non-hospitalized (estimated enrollment =1,050) patients are planned to be conducted at approximately 150 sites in the U.S., Brazil, Mexico, and Chile, and will evaluate virologic and clinical endpoints, with preliminary data expected later this summer. All trials are adaptively-designed, and the ultimate numbers of patients enrolled will depend on trial progress and insights from Phase 2 studies.

International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting, Including Exosomes, July 20-22: Plenary Speakers, Panel Sessions, Oral Abstract Talks, Poster Chats, & Educational Sessions; FOCUS: PLENARY SPEAKERS

The International Society for ExtracellularVesicles (ISEV) AnnualMeeting (ISEV2020), Including #Exosomes, Is Now VIRTUAL (July 20-22); and will feature over 600 Discussions (Plenary Addresses, Panel Sessions, Oral Abstract Talks, Poster Chats, & Educational Sessions). The program can viewed here ( and registration can be done here ( As eminent Yale professor Philip Askenase, MD, has said, “Exosomes are a sensational biological discovery and they seem to be involved in nearly all biological and clinical processes.” Please attend the virtual ISEV 2020 meeting to learn more about these fascinating and immensely important tiny particles. The 2020 virtual meeting will feature five plenary speakers who are acknowledged leaders in the field of extracellular vesicles (EVs). They are Alain Brisson, currently Emeritus Professor at the University of Bordeaux, in the team Extracellular Vesicles & Membrane Repair in CNRS unit CBMN; Hollis Cline, PhD, the Hahn Professor of Neuroscience and Co-Chair of the Department of Neuroscience at Scripps Research in La Jolla, California; Phylis Hanson, MD, PhD, the Minor J. Coon Collegiate Professor of Biological Chemistry and Chair of Biological Chemistry at the University of Michigan; Eduardo Marban, MD, PhD, Founding Director, Cedars-Sinai Heart Institute; and Shannon Stott, PhD, Assistant Professor, Massachusetts General Hospital Cancer Center, Department of Medicine, Harvard Medical School, Associate Member, Broad Institute. Additional information on each of the ISEV 2020 plenary speakers is provided below.


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