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Archive - Jul 2020

Date

July 6th

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 (https://osf.io/zm3ch/) posted online on July 1, 2020, Philip Askenase (https://medicine.yale.edu/news-article/15415/) (https://medicine.yale.edu/profile/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.

July 5th

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 (https://www.isev.org/mpage/2020Program) and registration can be done here (https://www.isev.org/mpage/2020Registration). 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.

ALAINE BRISSON, PHD

Label-Free Sensing of MCT1 and CD147 in Surface of Glioma-Derived Exosomes May Be Used for Tracking Metabolic Reprogramming and Malignant Progression in Glioma; Study Suggests Inhibitors of MCT1 & CD147 May Be Effective In Treating Gliomas

Researchers at the City University of Hong have demonstrated that malignant glioma cells release large numbers of exosomes containing high levels of MCT1 (monocarboxylate transporter 1) and its ancillary protein CD147 (cluster of differentiation 147). High levels of these two proteins are known to occur in malignant glioma and are associated with the tumor’s reprogramming to glycolysis (Warburg effect) as a rapid source of energy in a hypoxic environment. The authors showed that malignant glioma cells (GMs) release tremendous numbers of exosomes (nanovesicles of 30 nm to 200 nm in size), which promote tumor progression by the transport of pro-oncogenic molecules to neighboring cells. In their study, the authors found that hypoxia-induced malignant GMs strongly enhanced MCT1 and CD147 expression, playing a crucial role in promoting calcium-dependent exosome release. The hypoxic-GMs-derived exosomes contained significantly high levels of MCT1 and CD147, which could be quantitatively detected by noninvasive localized surface plasmon resonance (LSPR) and atomic force microscopy (AFM) biosensors, demonstrating that MCT1 and CD147 could be used as precise surrogate biomarkers for tracking parent GMs’ metabolic reprogramming and malignant progression as liquid biopsies. These new results were published on June 26, 2020 in Science Advances. The open-access article is titled “Label-Free Sensing of Exosomal MCT1 And CD147 for Tracking Metabolic Reprogramming and Malignant Progression in Glioma.” In the introduction to this article, the authors noted that glioma is the most common type of brain cancer and that it originates predominantly from neuroglial stem cells.

July 4th

Protective Antibodies Identified for Rare, Polio-Like Disease in Children

Researchers at Vanderbilt University Medical Center, Purdue University and the University of Wisconsin-Madison have isolated human monoclonal antibodies that potentially can prevent a rare, but devastating, polio-like illness in children linked to a respiratory viral infection. The results have been published as the cover story of the July 3, 2020 issue of Science Immunology, and the article is titled “Human Antibodies Neutralize Enterovirus D68 and Protect Against Infection and Paralytic Disease.” The illness, called acute flaccid myelitis (AFM), causes sudden weakness in the arms and legs following a fever or respiratory illness. More than 600 cases have been identified since the U.S. Centers for Disease Control and Prevention (CDC) began tracking the disease in 2014. There is no specific treatment for AFM, which tends to strike in the late summer or early fall, and which has been associated with some deaths. However, the disease has recently been linked to a group of respiratory viruses called enterovirus D68 (EV-D68). Researchers at the Vanderbilt Vaccine Center isolated antibody-producing blood cells from the blood of children who had previously been infected by EV-D68. By fusing the blood cells to fast-growing myeloma cells, the researchers were able to generate a panel of monoclonal antibodies that potently neutralized the virus in laboratory studies. Colleagues at Purdue determined the structure of the antibodies, which shed light on how they specifically recognize and bind to EV-D68. One of the antibodies protected mice from respiratory and neurologic disease when given either before or after infection by the enterovirus.

CytoDyn Announces Execution of Exclusive Agreement with American Regent for Distribution and Supply of Leronlimab for Treatment of COVID-19 in United States, Pending Trial Results & FDA Approval

On July 3, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced that it has signed an exclusive Distribution and Supply Agreement with American Regent, Inc. (“American Regent”) (https://www.americanregent.com/) for the distribution of leronlimab for the treatment of COVID-19 in the United States. Under the terms of the agreement, CytoDyn will supply leronlimab for the treatment of COVID-19 for distribution by American Regent and receive quarterly payments based on a profit-sharing arrangement. “Having this distribution agreement in place ahead of the readout from CytoDyn’s COVID-19 clinical trials further emphasizes CytoDyn’s commitment to making leronlimab immediately available to patients based on the successful completion of its ongoing clinical trials,” said Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn. “We are particularly happy to be partnering with a company with the proven expertise, unparalleled commercial reach, and stellar reputation of American Regent.” “American Regent is looking forward to partnering with CytoDyn to provide COVID-19 patients rapid and efficient access to a potentially life-saving drug,” said Mr. Harsher Singh, American Regent’s Vice President and Chief Commercial Officer. CytoDyn is currently enrolling a Phase 2b/3 clinical trial for 390 severe and critically ill COVID-19 patients, which is a randomized, placebo-controlled trial with 2:1 ratio (active drug to placebo ratio). CytoDyn has also completed its enrollment of a Phase 2 randomized clinical trial with 75 patients in the mild-to-moderate COVID-19 population. CytoDyn has been granted more than sixty emergency Investigational New Drug (eIND) authorizations by the U.S.

CytoDyn CEO on DrBeen Webcast July 4, 2020 (9 pm EDT) (YouTube & FB) to Discuss with Mobeen Syed, MD, the Many Potential Opportunities for Anti-CCR5 Monoclonal Antibody Leronlimab, Including Treatment of COVID-19, HIV, & Triple-Negative Breast Cancer

CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing leronlimab (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, has announced that Nader Pourhassan, PhD, President and Chief Executive Officer of CytoDyn will be interviewed on the DrBeen webcast hosted by Mobeen Syed, MD, on Saturday, July 4, 2020 at 9:00 pm EDT (6 pm PDT, 7 pm MDT, and 8 pm CDT). The interview will be available simultaneously on two channels:

YouTube - DrBeen Medical Lectures
Link: https://www.youtube.com/c/USMLEOnline

Facebook: DrBeen Medical
Link: https://m.facebook.com/drbeenmedical

CYTODYN & CORONAVIRUS DISEASE 2019(COVID-19): CytoDyn has met its 75-patient enrollment target in its Phase 2 clinical trial for COVID-19, a randomized clinical trial for mild-to-moderate COVID-19 population in the U.S. and enrollment continues in CytoDyn’s Phase 2b/3 randomized clinical trial for severe and critically ill COVID-19 population in several hospitals throughout the country. SARS-CoV-2 was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. The origin of SARS-CoV-2 causing the COVID-19 disease is uncertain, and the virus is highly contagious. COVID-19 typically transmits person to person through respiratory droplets, commonly resulting from coughing, sneezing, and close personal contact. Coronaviruses are a large family of viruses, some causing illness in people and others that circulate among animals. For confirmed COVID-19 infections, symptoms have included fever, cough, and shortness of breath. The symptoms of COVID-19 may appear in as few as two days or as long as 14 days after exposure. Clinical manifestations in patients have ranged from non-existent to severe and fatal. At this time, there are minimal treatment options for COVID-19.

July 3rd

Gene Mutations That Cause Familial Mediterranean Fever (FMF) May Convey Resistance to Bubonic Plague; FMF Mutations in Gene for Inflammation Protein Pyrin Associated with Plague Resistance

Researchers have discovered that Mediterranean populations may be more susceptible to an autoinflammatory disease because of evolutionary pressure to survive the bubonic plague. The study, carried out by scientists at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, determined that specific genomic variants that cause a disease called familial Mediterranean fever (FMF) may also confer increased resilience to the plague. The researchers suggest that because of this potential advantage, FMF-causing genomic variants have been positively selected for in Mediterranean populations over centuries. The findings were published online on June 29, 2020 in Nature Immunology. The article is titled “Ancient Familial Mediterranean Fever Mutations in Human Pyrin and Resistance to Yersinia pestis.” Over centuries, a biological arms race has been fought between humans and microbial pathogens. This evolutionary battle is between the human immune system and microorganisms trying to invade our bodies. Microbes affect the human genome in many ways. For example, they can influence some of the genomic variation that accumulates in human populations over time. "In this era of a new pandemic, understanding the interplay between microbes and humans is ever critical," said Dr. Dan Kastner, MD, PhD, NHGRI Scientific Director and a co-author on the paper. “We can witness evolution playing out before our very eyes.” One such microbe is Yersinia pestis, the bacterial agent responsible for a series of well-documented bubonic plague (https://www.cdc.gov/plague/faq/index.html) epidemics that led to over 50 million deaths.

Some Animals Can, Indeed, Sense Coming Earthquakes Ahead of Time, New Study Suggests; Future Work Will Pursue Development of Early-Warning Systems Harnessing This “Sixth Sense” of Animals

Even today, nobody can reliably predict when and where an earthquake will occur. However, eyewitnesses have repeatedly reported that animals behave unusually before an earthquake. In an international cooperation project, researchers from the Max Planck Institute of Animal Behavior in Konstanz/Radolfzell and the Cluster of Excellence Centre for the Advanced Study of Collective Behaviour at the University of Konstanz, have investigated whether cows, sheep, and dogs can actually detect early signs of earthquakes. To do so, they attached sensors to the animals in an earthquake-prone area in Northern Italy and recorded their movements over several months. The movement data show that the animals were unusually restless in the hours before the earthquakes. The closer the animals were to the epicenter of the impending quake, the earlier they started behaving unusually. The movement profiles of different animal species in different regions could therefore provide clues with respect to the place and time of an impending earthquake. You may watch a video about the research project in campus.kn, the online magazine of the University of Konstanz: https://www.campus.uni-konstanz.de/en/science/the-sixth-sense-of-animals.... Please see details of the new research below. The results were published online on June 3, 2020 in Ethology. The open-access article is titled ““Potential Short-Term Earthquake Forecasting by Farm-Animal Monitoring” (https://onlinelibrary.wiley.com/doi/full/10.1111/eth.13078). Experts disagree about whether earthquakes can be exactly predicted. Nevertheless, animals seem to sense the impending danger hours in advance. For example, there are reports that wild animals leave their sleeping and nesting places immediately before strong quakes and that pets become restless.