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Moderna Announces Beginning of Phase 3 COVE Study of mRNA Vaccine Against COVID-19 (mRNA-1273); Study Expected to Enroll 30,000 Participants in US

On July 27, 2020, Moderna, Inc., (Nasdaq: MRNA) a clinical-stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, announced that the Phase 3 study of its mRNA vaccine candidate (mRNA-1273) against COVID-19 has begun dosing participants. The Phase 3 study, called the COVE (Coronavirus Efficacy) study, is being conducted in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) and the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services. “We are pleased to have started the Phase 3 COVE study,” said Stephane Bancel, MBA, CEO at Moderna. “We are grateful to the efforts of so many inside and outside the company to get us to this important milestone. We are indebted to the participants and investigators who now begin the work of the COVE study itself. We look forward to this trial demonstrating the potential of our vaccine to prevent COVID-19, so that we can defeat this pandemic.” The Phase 3 study protocol follows the U.S. FDA guidance on clinical trial design for COVID-19 vaccine studies. The randomized, placebo-controlled trial is expected to include approximately 30,000 participants in the United States, testing an mRNA-1273 dosage of 100 µg. The primary endpoint will be the prevention of symptomatic COVID-19 disease. Key secondary endpoints include prevention of severe COVID-19 disease (as defined by the need for hospitalization) and prevention of infection by SARS-CoV-2, regardless of symptomology. SARS-CoV-2 is the virus that causes COVID-19.

Gene in Fat Plays Key Role in Insulin Resistance; “Getting Better Grasp on Function of KBTBD2 Could Open Completely New Window into How Insulin Sensitivity Is Regulated,” Says Nobelist Who Made Seminal “Innate Immunity” Discovery of Toll-Like Receptors

Deleting a key gene in mice in just their fat made tissues throughout these animals insulin-resistant, in addition to other effects, a new study by University of Texas Southwestern (UTSW) researchers shows. The findings, initially published online on May 7, 2020 in PNAS (https://www.pnas.org/content/117/21/11829), could shed light on Type 2 diabetes and other insulin-resistance disorders, which remain poorly understood, despite decades of study. The open-access article is titled “Tissue-Specific Disruption of Kbtbd2 Uncovers Adipocyte-Intrinsic and -Extrinsic Features of the teeny Lipodystrophy Syndrome.” In 2016, UTSW immunologist and geneticist and Nobel Laureate Bruce Beutler (photo), MD, (https://profiles.utsouthwestern.edu/profile/10593/bruce-beutler.html, Zhao Zhang, PhD (https://profiles.utsouthwestern.edu/profile/155419/zhao-zhang.html, and their colleagues reported a new mouse mutant that they named teeny (https://www.pnas.org/content/113/42/E6418), which resulted from inactivating a gene known as KBTBD2 that is widely expressed throughout the body in mice and humans. In addition to these animals’ small size – about half that of normal “wild-type” mice – the scientists quickly noticed that teeny mice produce a lot of urine, often a sign of diabetes. Dr. Beutler is a Regental Professor and Director of the Center for the Genetics of Host Defense (https://www.utsouthwestern.edu/education/medical-school/departments/gene...). Dr. Zhang is an Assistant Professor of Internal Medicine who also has an appointment in the Center. Sure enough, tests showed that these teeny animals had extremely high blood sugar, severe insulin resistance, and high insulin levels that peaked at 8 weeks of age and then gradually declined. They also had abnormally low amounts of body fat, but had fatty livers.

Election of Next President & Riveting Plenary Address Highlight Day 2 of International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22)

Tuesday, July 21, witnessed the election of new ISEV President Clotilde Théry (photo) (https://en.wikipedia.org/wiki/Clotilde_Th%C3%A9ry), PhD, of the Institut Curie in Paris, and an electrifying scientific presentation on work involving exosomes, cardiology, and Duchenne muscular dystrophy (DMD), as two of many highlights of an action-packed Day 2 of the International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/). This year’s ISEV meeting has successfully gone virtual with 1,600 virtual attendees from 52 countries around the world, and is offering ~600 presentations of various types (Plenary Addresses, “Hot-Topic” Panel Sessions, Featured Abstracts, Oral Abstract Talks, Poster Chats, & Education Sessions), both live-streamed and on-demand, to its large international group of participants. Tuesday’s activities included the meeting’s third Plenary Address, presentation of the third of four ISEV Featured Abstracts, the ISEV General Assembly meeting at which new ISEV President Clotilde Thery was elected and three ISEV Special Achievement Awards were presented, the holding of highly informative Education Sessions 3 & 4, and presentations of key current technology by ISEV 2020’s Gold Sponsors. The meeting’s third Plenary Address, “Deconstructing Regenerative Medicine: From Cells to Exosomes and Defined Factors,” was delivered by Eduardo Marbán, MD, PhD, Founding Director, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles. Dr. Marbán is an international leader in cardiology and a pioneering heart researcher. His 30-plus years of experience in patient care and research have led to key discoveries in gene and stem cell therapies for heart disease. Those discoveries have formed the basis for multiple startup companies. Dr.

“EVs in Neurological Diseases,” with Focus on Rett Syndome, Is Second Plenary Address on Opening Day of International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22) for 1,600 Virtual Attendees from 52 Countries

(Written for BioQuick News by Michael A. Goldman, PhD, Professor & Former Chair, Biology, San Francisco State University, https://faculty.sfsu.edu/~goldman/) The International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), with a record 1,600 virtual attendees from 52 countries around the world, and offering ~600 presentations of various types (Plenary Addresses, “Hot-Topic” Panel Sessions, Featured Abstracts, Oral Abstract Talks, Poster Chats, & Education Sessions), both live-streamed and on-demand, showcased its second Plenary Address on Monday, July 20. This address was titled “EVs in Neurological Diseases,” and was delivered by Hollis Cline (photo), PhD, the Hahn Professor of Neuroscience and Co-Chair of the Department of Neuroscience at Scripps Research in La Jolla, California, USA. Dr. Cline (https://www.scripps.edu/faculty/cline/) is also a Counselor for the National Institute of Neurological Disorders and Stroke (NINDS) and a Past President of the Society for Neuroscience. She received her BA from Bryn Mawr College and her PhD from the University of California at Berkeley, followed by postdoctoral training at Yale University and Stanford University. Dr. Cline has served on the faculty of the University of Iowa and the Cold Spring Harbor Laboratory, where she served as the Director of Research from 2002-2006. Dr. Cline’s research has demonstrated the roles of a variety of activity-dependent mechanisms in controlling structural plasticity of neuronal dendrites and axons, synaptic maturation, and topographic map formation. This body of work has helped to generate a comprehensive understanding of the role of experience in shaping brain development.

Fourth Featured Abstract at ISEV 2020 Virtual Annual Meeting Reports That, Following Endocytosis by Acceptor Cells, Extracellular Vesicles (EVs) Release Their Cargo from Endosomes; New Analytical Methodology Enables Key Finding

Today (Wednesday, June 22), in the last of four Featured Abstracts presented by graduate students during the ISEV 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Bhagyashree Joshi (photo), of the Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, The Netherlands, presented her group’s abstract (FA03) “Genetically Encoded Probes Provide Insight into Extracellular Vesicle Cargo Release in Cells.” Ms. Joshi is a PhD candidate in the laboratory of Inge Zuhorn, PhD, Associate Professor, Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen University Medical Center Groningen. In her introduction, Ms. Joshi noted that extracellular vesicles (EVs) are known to modulate tissue development, regeneration, and disease through the transfer of proteins, nucleic acids, and lipids between cells. Currently, however, the mechanism of cytosolic delivery of EV cargo is largely unknown, she said. It has been speculated that EVs undergo back fusion at multi-vesicular bodies (MVBs) in recipient cells to release their functional cargo. However, Ms. Joshi said, evidence for this is lacking. She remarked that tracing the cellular uptake of EVs with high resolution, as well as acquiring direct evidence for the release of EV cargo, is challenging, chiefly because of technical limitations. To address this problem, Ms. Joshi and colleagues developed an analytical methodology that combined state-of-the-art molecular tools and correlative light and electron microscopy (CLEM) to identify the intracellular site for EV cargo release. Green fluorescent protein (GFP) was loaded inside EVs through the expression of GFP-CD63, a fusion of GFP to the cytosolic tail of CD63, in EV producer cells.

Third Featured Abstract at ISEV 2020 Virtual Annual Meeting Reports That Expression of Tetraspanin 8 (Tspan8) Causes Nuclear Proteins to Be Incorporated into Tumor-Derived Extracellular Vesicles (EVs); Results Suggest New Mechanism of Action for Tspan8

On Tuesday, June 21, in the third of four Featured Abstracts being presented by junior investigators during the ISEV 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Elena Grueso Navarro (photo), a Marie Curie Fellow at TRAIN-EV* at the Institute for Infection Prevention and Hospital Epidemiology, Medical Center-University of Freiburg, Breisgau, German, presented her group’s abstract (FA02) “Nuclear Proteins Are Recruited into Tumor-Derived Extracellular Vesicles Upon Expression of Tetraspanin Tspan8.” Ms. Navarro is a PhD candidate in the laboratory of Irina Nazarenko, PhD, Head, Exosomes & Tumor Group, Institute for Infection Prevention and Hospital Epidemiology, Medical Center-University of Freiburg. In her introduction, Ms. Grueso Navarro noted that tetraspanin 8 (Tspan8) is a transmembrane protein that exhibits a unique expression pattern, being overexpressed in many cancer types, but undetectable in a majority of healthy tissues. When overexpressed, Tspan8 facilitates cell motility, and, in tumor models, it supports invasion and metastasis. In addition, Tspan8 is recruited to the extracellular vesicles (EVs). Previous work in Dr. Nazarenko's laboratory has shown that Tspan8 affects EV content and mediates the EVs’ function in metastasis and angiogenesis. These data suggest that Tspan8 may be a promising therapeutic target in cancer.

Four Studies by Students/Fellow in Professor Lorraine O’Driscoll’s Laboratory at Trinity College Dublin Are Presented at International Society for Extracellular Vesicles (ISEV) 2020 Virtual Annual Meeting (July 20-22)

Professor Lorraine O’Driscoll (photo), PhD, is Professor in Pharmacology and Irish Research Council Advanced Laureate at the School of Pharmacy and Pharmaceutical Sciences, and the Trinity Biomedical Sciences Institute of Trinity College Dublin in Ireland. Dr. O’Driscoll (https://pharmacy.tcd.ie/staff/odriscoll-cv.php?uname=lodrisc) (https://www.tcd.ie/research/profiles/?profile=lodrisc) is also the Coordinator and Principal Investigator of the TRAIN-EV Program (http://train-ev.eu/), which provides training to 15 PhD students in extracellular vesicles (EVs) for benefit in health and disease. Dr. O’Driscoll’s research group focuses on diagnostic, prognostic, and predictive biomarkers; discovering new therapeutic targets; cancer cells’ communication via extracellular vesicles (EVs), as well as the potential uses of EVs from mesenchymal stem cells (MSCs) in regenerative medicine and improving infant milk formula (IMF) by understand milk EVs. Three of Dr. O’Driscoll’s PhD students and one of her post-doctoral research fellows are presenting posters at the International Society for Extracellular Vesicles (ISEV) Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/). These four posters focus on EV release in triple-negative breast cancer, EV release inhibition in prostate cancer, analysis of EVs from drug-resistant and drug-sensitive cancer cells as potential predictive biomarkers in liquid biopsy, and optimizing methods for the separation and characterization of EVs from skim milk and infant milk formula. PhD student Niamh McNamee presented a poster (PF08.02) titled “Inhibition of Extracellular Vesicles in Triple-Negative Breast Cancer.” In her introduction, Ms. McNamee noted that triple-negative breast cancer (TNBC) is the most aggressive from of breast cancer.

Exosomes That Are Both Antigen-Specific & Carry a Selected Gene-Regulating miRNA Act at the Immune Synapse to Induce APC-Derived Secondary Suppressive Exosomes, A Unique Approach That May Have Treatment Applications in Cancer, Autoimmunity, & Allergy

At the International Society for Extracellular Vesicles 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Philip Askenase, MD, presented a poster (PT09.16) titled “Unique Dual Targeting Antigen-Specific and Delivered Chosen-Gene-Specific Regulating Primary Exosomes Acting at the Immune Synapse to Induce APC-Derived Secondary Effector T Cell Suppressive Exosomes.” Dr. Askenase is 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. In the ISEV poster, Dr. Askenase and colleagues report identification of a multi-exosome-APC (antigen-presenting cell) circuit that may be applicable far beyond the skin immunity these scientists study in mice. The researchers show results indicating they have been able to induce therapeutic exosomes that both specifically target a particular antigen on acceptor cells like APCs due to antibody light chains bound to the surface of the exosomes, and also target specific gene functions of the acceptor cells, due to delivery, in the exosome’s cargo, of a selected microRNA (miRNA). This dual antigen-specific (via the surface-bound antibody light chains) and gene-specific (via the exosome-associated selected miRNA) therapy may have applications in the treatment of cancer, autoimmunity, and allergy. In order to demonstrate this capability experimentally, Dr.

Second of Four Featured Abstract at ISEV 2020 Virtual Annual Meeting (July 20-22) Describes Initial Results of Efforts to Develop Reference Intervals for Extracellular Vesicles (EVs) in Human Plasma by Flow Cytometry

On Monday, June 20, in the second of four Featured Abstracts being presented by junior investigators during the ISEV 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Bo Li (photo), PhD, from the Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China (People’s Republic), presented her group’s abstract (FA04) “Towards Reference Intervals of Extracellular Vesicles in Human Plasma by Flow Cytometry.” In her introduction, Dr. Li noted that, although flow cytometers with submicrometer sensitivity can characterize single extracellular vesicles (EVs) in clinical samples, there is no consensus about the concentrations of EVs in plasma from healthy humans. To determine cut-off values for diagnoses, reference intervals of EVs in plasma are needed, Dr. Li asserted. To establish such reference intervals, Dr. Li said there are four requirements. First, a significant number of healthy donors should be included. Secondly, the presence of non-EV particles, residual platelets, lipoproteins, and hemolysis should be quantified. Thirdly, a clinically applicable protocol to avoid swarm detection should be established in advance. And lastly, flow cytometry signals should be in SI units. Dr. Li said that the long-term aim of this study is to determine reference intervals of EV concentrations in human plasma within known dynamic ranges of the detectors. In the experimental work to establish a clinical reference, Dr. Li and colleagues first collected blood from 224 healthy volunteers and prepared platelet-free plasma. Then, they performed quality-control measurements including residual platelet count, serum index, and lipid spectrum. They also determined that a protocol of 31-fold to 10(3) dilution is safe to prevent swarm detection in plasma from healthy donors.

First of Four Featured Abstracts at ISEV 2020 Virtual Annual Meeting (July 20-July 22) Focuses on How Ral-GTPases Promote Metastasis by Controlling Biogenesis & Organotropism of Exosomes; Breast Cancer Metastasis to Lung Is Subject of Study

On Monday, June 20), in the first of four Featured Abstracts being presented by junior investigators during the ISEV 2020 Virtual Annual Meeting (July 20-22) (https://www.eventscribe.com/2020/ISEV/), Shima Ghoroghi (photo), from Dr. Jacky Goetz’s Laboratory for Tumor Mechanics (http://www.goetzlab.com/team/), University of Strasbourg, France, delivered abstract FA01 “Ral-GTPases Promote Metastasis by Controlling Biogenesis and Organotropism of Exosomes.” Ms. Ghoroghi joined Dr. Goetz’s group as a PhD student in 2016 to study the role of Ral-GTPases in the secretion of exosomes by tumor cells during metastasis under close supervision of Dr. Vincent Hyenne, a specialist in exosomes. In her introduction, Ms. Ghoroghi noted that exosomes are small vesicles of endosomal origin, composed of different biomolecules including RNA, lipids, and proteins, which can be taken up by distant cells and deliver a functional message. Many studies have shown that exosomes play a major role in tumor progression by mediating the communication between tumors cells and their microenvironment. The main goals of Ms. Ghoroghi’s PhD project consist in dissecting the mechanisms of exosome secretion influenced by Ral-GTPases and understanding the importance of these exosomes in metastasis. During her PhD studies, Ms. Ghoroghi found that Ral-GTPases are central molecules linking the mechanisms of exosome secretion to their capacity to disseminate and induce pre-metastatic niches. She provided a detailed dissection of the impact of the Ral-GTPases on exosome secretion levels and content. She also showed that Ral-GTPases control exosome secretion by acting on the endosomal secretion pathway through the phospholipase D1 (PLD1), which also promotes exosome secretion.

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