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June 3rd, 2020

Optimal Time to Treat Huntington’s Disease ID'd; Abnormally High Levels of Neurofilament Light (NfL) Biomarker Detectable 24 Years Before Onset of Clinical Symptoms; Marker Could Be Used to Monitor & Gauge Effectiveness of Future Treatments

The earliest brain changes due to Huntington’s disease can be detected 24 years before clinical symptoms show, according to a new University College London (UCL)-led study. The researchers say their findings, published in the June 1, 2020 issue of The Lancet Neurology (https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(20)30143-5/fulltext), could help with clinical trials by pinpointing the optimal time to begin treating the disease. The open-access article is titled “Biological and Clinical Characteristics of Gene Carriers Far from Predicted Onset in the Huntington's Disease Young Adult Study (HD-YAS): A Cross-Sectional Analysis.” There is currently no cure for Huntington’s, a hereditary neurodegenerative disease, but recent advances in genetic therapies hold great promise. Researchers would ultimately like to treat people before the genetic mutation has caused any functional impairment. However, until now, it was unknown when the first signs of damage emerge--but because there is a genetic test for Huntington’s susceptibility, researchers have a unique opportunity to study the disease before symptoms appear. Professor Sarah Tabrizi (photo), MD, PhD, (https://en.wikipedia.org/wiki/Sarah_Tabrizi) (UCL Huntington’s Disease Centre, UCL Queen Square Institute of Neurology), the study lead, said: “Ultimately, our goal is to deliver the right drug at the right time to effectively treat this disease – ideally we would like to delay or prevent neurodegeneration while function is still intact, giving gene carriers many more years of life without impairment.” “As the field makes great strides with the drug development, these findings provide vital new insights informing the best time to initiate treatments in the future, and represent a significant advance in our understanding of early Huntington’s.”

June 2nd

Cancer Cells Cause Inflammation to Protect Themselves from Oncolytic Viruses

Researchers at the Francis Crick Institute in the UK have uncovered how cancer cells protect themselves from oncolytic viruses that are harmful to tumors, but not to healthy cells. These findings could lead to improved viral treatments for cancers. In their study, published online on June 1, 2020 in Nature Cell Biology (https://www.nature.com/articles/s41556-020-0527-7), the researchers identified a mechanism that protects cancer cells from oncolytic viruses, which preferentially infect and kill cancer cells. The article is titled “Cancer Cells Cause Inflammation to Protect Themselves from Viruses.” These oncolytic viruses are sometimes used as a treatment to destroy cancer cells and stimulate an immune response against the tumor. However, they only work in a minority of patients and the reasons why they are effective or not are not yet fully understood. The research team examined the environment surrounding a tumor and how cancer cells interact with their neighbors, in particular, with cancer-associated fibroblasts (CAFs) (https://en.wikipedia.org/wiki/Cancer-associated_fibroblast), which researchers know play a significant role in cancer protection, growth, and spread. The researchers found that when cancer cells are in direct contact with CAFs, this leads to inflammation that can alert the surrounding tissue, making it harder for viruses to invade and replicate within the cancer cell. This protective inflammatory response occurs when cancer cells pass small amounts of their cytoplasm through to the CAFs. This triggers the fibroblasts to signal to nearby cells to release cytokines, molecules that cause inflammation.

Moderna Announces First Participants in Each Age Cohort Have Been Dosed in Phase 2 Study of mRNA Vaccine (mRNA-1273) Against SARS-CoV-2; Phase 2 Study Expected to Enroll 600 Participants; Phase 3 Study Expected to Begin in July 2020

On May 29, 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 first participants in each age cohort have been dosed in the company’s Phase 2 study (https://clinicaltrials.gov/ct2/show/NCT04405076?term=NCT04405076&draw=2&...) of its mRNA vaccine candidate (mRNA-1273) against the novel coronavirus (SARS-CoV-2) that causes COVID-19. This Phase 2 study, being conducted by Moderna under its own Investigational New Drug (IND) application, will evaluate the safety, reactogenicity, and immunogenicity of two vaccinations of mRNA-1273 given 28 days apart. The company intends to enroll 600 healthy participants across two cohorts of adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300). Each participant will be assigned to receive placebo, a 50 μg or a 100 μg dose at both vaccinations. Participants will be followed through 12 months after the second vaccination. Given the 25 μg and 100 μg dose levels in the Phase 1 study showed neutralizing antibody titers at or above convalescent sera and were generally well tolerated, the company has decided not to pursue the 250 μg dose level in the Phase 2 study. On May 6, 2020, the U.S. Food and Drug Administration (FDA) completed its review of the Moderna’s IND application for mRNA-1273 and on May 12, 2020, the FDA granted this vacccine Fast Track designation. On May 18, 2020, Moderna announced (http://www.bioquicknews.com/node/5369) initial data from the Phase 1 study of mRNA-1273 led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). The NIH will be submitting the Phase 1 data to a peer-reviewed clinical publication.

Elevated Levels of Neurofilament Light (NfL) Detected in Plasma and Exosomes of Those with Repetitive Mild Traumatic Brain Injuries (mTBIs); Testing of NfL Biomarker Levels May Enable Early Intervention to Address Associated PTSD & Depression

A blood test may help researchers understand which people may take years to recover from concussion, according to a study published in the May 27, 2020 online issue of Neurology®, the medical journal of the American Academy of Neurology. The Neurology article is titled “Exosomal Neurofilament Light--A Prognostic Biomarker for Remote Symptoms After Mild Traumatic Brain Injury?” The study looked at a biomarker called neurofilament light (NfL) chain, a nerve protein that can be detected in the blood when nerve cells are injured or die. Researchers found that, years later, people with a history of three or more concussions were more likely to have high levels of the biomarker than people who had not had a concussion. High levels of the biomarker were also associated with more severe symptoms such as post-traumatic stress disorder and depression years after the concussions occurred. “While most people with mild concussions recover completely, some never get their lives back fully because of chronic disability,” said one of the study’s authors, Kimbra L. Kenney, MD, of the National Intrepid Center of Excellence, Walter Reed National Military Medical Center, Bethesda, Maryland, and a Fellow of the American Academy of Neurology (AAN). “These people may benefit greatly from a test that could predict those disabilities years ahead of time. Our study found there’s great potential for this protein to predict the problems people with concussions may experience years after their injuries.” The study involved 195 military veterans with an average age of 38; 85 percent were male. Participants were divided into three groups: 45 people with no history of concussions, 94 people with one or two concussions, and 56 people with three or more concussions. It had been at least seven years since the last concussion for the participants.

Achilles Therapeutics, An Immunotherapy Spin-Out from Francis Crick Institute and UCL Cancer Institute, Targets Clonal Neoantigens in New Personalized Therapy for Melanoma

On May 29, 2020, it was announced that Achilles Therapeutics(https://achillestx.com/), a UK-based company built on the research of Francis Crick institute (https://www.crick.ac.uk/)G roup Leader Charles Swanton (https://www.crick.ac.uk/research/find-a-researcher/charles-swanton), PhD, and Sergio Quezada (https://www.cancerresearchuk.org/our-research/researchers/dr-sergio-quezada), PhD, and Karl Peggs (https://www.uclh.nhs.uk/OurServices/Consultants/Pages/DrKarlPeggs.aspx), MD, at the University College London (UCL) Cancer Institute (https://www.ucl.ac.uk/cancer/), has started a clinical trial for a new personalized immunotherapy for patients with melanoma. The Phase I/II trial is testing a clonal neoantigen T cell (cNeT) therapy in approximately 20 patients with recurrent or metastatic melanoma. The first patient to take part in this trial received treatment in the week of this announcement. This new therapy uses T lymphocytes to target cancer-cell-surface antigens coded for by DNA mutations present in all the cancer cells of a cancer in a particular patient, regardless of where these cancer cells are in the body. This is possible because, while a cancer grows in a particular patient and mutates its DNA, all the resulting cancer cells in that patient retain the earliest mutations present in the trunk of the tumor’s evolutionary tree, and some of these mutations code for antigens that are expressed on the cancer cell surface. These are called clonal neoantigens. T lymphocytes recognize these markers as a sign that they need to attack the cell. The researchers will carefully select the particular lymphocytes used for each patient that recognize these clonal neoantigens that are unique to each person’s cancer.

27 Proteins in Blood of COVID-19 Patients ID’d by Mass Spec Approach As Potential Biomarkers to Predict Disease Severity and Possibly Direct Different Courses of Treatment

Researchers at the Francis Crick Institute (https://www.crick.ac.uk/) in the UK and the Charité – Universitätsmedizin Berlin (https://www.charite.de/en/), together with colleagues at additional institutions, have identified 27 protein biomarkers that could be used to predict whether a patient with COVID-19 is likely to become severely ill with the disease. People infected with SARS-CoV-2, the RNA virus that causes COVID-19, respond differently. Some do not develop any symptoms, some need to be hospitalized and, for some, the disease is fatal. In this study, published online on June 1, 2020 in Cell Systems (https://www.cell.com/cell-systems/fulltext/S2405-4712(20)30197-6/), researchers found 27 potential biomarkers that are present at different levels in patients with COVID-19, depending on the severity of their symptoms. The markers could help doctors to predict how ill a patient will become and provide scientists with new targets for drug development. The open-access Cell Systems article is titled “Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection.” The researchers refined a mass spectrometry (MS) analysis method to rapidly test for the presence and quantity of various proteins in the blood plasma. This MS platform was developed at the Francis Crick Institute and applied to analyze serum of 31 COVID-19 patients at the Berlin University Hospital Charité. The results were further validated in 17 additional patients with COVID-19 at the same hospital and in 15 healthy people. The researchers hope their findings will lead to the development of simple routine tests to check for the levels for one or some of these proteins in patients with COVID-19. The results of such tests could be used to support doctors in deciding what treatment to give.

Antiviral Inhibitor (Avifavir) of RNA-Dependent RNA Polymerase Approved for Use in Russia Hospitals for Treatment of COVID-19 Caused by RNA Virus SARS-CoV-2; Modified Drug Based on Japan’s Anti-Influenza Drug Favipiravir Is Administered in Tablet Form

On June 1, 2020, in Moscow, the Russian Direct Investment Fund (RDIF), Russia’s sovereign wealth fund, and the ChemRar Group (a pharmaceutical development company) announced that they will deliver 60,000 doses of Avifavir to Russian hospitals in June. Avifavir is Russia’s first anti-COVID-19 drug and has, according to the RDIF and ChemRar Group, shown high efficacy in treating patients with coronavirus during ongoing clinical trials. Avifavir received a registration certificate from the Ministry of Health of the Russian Federation on Saturday, May 30. Thus, Avifavir has become the first Favipiravir-based drug in the world approved for the treatment of COVID-19. Favipiravir (https://en.wikipedia.org/wiki/Favipiravir) is an antiviral drug that inhibits the action of RNA-dependent RNA polymerases of RNA viruses. Favipiravir was developed by Toyami Chemical in order to inhibit RNA replication of the influenza virus, an RNA virus, as is SARS-CoV-2, and was approved for medical use in Japan in 2014. Favipiravir continues to be marketed for influenza in Japan, under the brand name Avigen, and it became a generic drug in 2018. In addition, Japan is currently trialing Avigen for the treatment of COVID-19, but Avigen has not yet been approved for this use in Japan. Russian chemists have slightly modified the original Favipiravir molecule (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) to make it more effective in COVID-19 and the Russian version of this drug has been named Avifavir. A PR spokesman for the RDIF (Arseniy Palagin, Press Secretary, RDIF) told BioQuick News that the specific modifications in Avifavir will be described later. In addition, Mr.

Extracellular Vesicles (EVs) Play Key Role in Pathology of Malaria Caused by Plasmdium vivax; EVs Promote Adherence of Parasites to Cells in Spleen, Where Parasites Can Remain “Hidden” and Cause Severe Disease Despite Low Parasitemia in Peripheral Blood

Plasmodium vivax is the most widely distributed human malaria parasite, mostly outside sub-Saharan Africa, and responsible for millions of clinical cases yearly, including severe disease and death. The mechanisms by which P. vivax causes disease are not well understood. Recent evidence suggests that, similar to what has been observed with the more lethal Plasmodium falciparum, red blood cells infected by the parasite may accumulate in internal organs and that this could contribute to the pathology of the disease. In fact, the team led by Hernando A. del Portillo, PhD, and Carmen Fernández-Becerra, PhD, both of the Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, recently showed that P. vivax-infected red blood cells adhere to human spleen fibroblasts thanks to the surface expression of certain parasite proteins, and that this expression is induced by the spleen itself. "These findings indicate that the spleen plays a dual role in malaria vivax," says ICREA (Catalan Institution for Research and Advanced Studies) researcher Dr. del Portillo. "On one hand, it eliminates infected red blood cells. On the other hand, it may serve as a "hiding" place for the parasite." This could explain why P. vivax can cause severe disease in spite of low peripheral blood parasitemia.” The new results were reported online on June 2, 2020 in Nature Communications.

June 1st

World Milk Day Today! Expert Comments on Nutritional & Infection-Fighting Benefits of Milk Exosome Supplements, Particularly for Premature Infants & Infants in Developing Countries & For All Infants Worldwide

[On World Milk Day (June 1), the US Department of Agriculture (USDA) hosted a commentary by scientist Janos Zempleni, PhD, Willa Cather Professor of Molecular Nutrition, Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, who enthused about the potential benefits of supplementing infant formula with small, benefit-rich nanoparticles (exosomes) from milk. Dr. Zempleni’s commentary follows.] Today is World Milk Day! In the United States, the average annual consumption of milk is approximately 146 pounds (17 gallons) per person, according to data from USDA’s Economic Research Service (https://www.ers.usda.gov/data-products/dairy-data/dairy-data/). Children account for a large portion of milk drinkers, particularly infants, as milk is meant to be the sole source of nutrition for infants until age 6 months. Milk naturally contains infection-fighting properties. Commercial baby formula usually does not. Funding from the USDA’s National Institute of Food and Agriculture and other sponsors has allowed me to explore an element of milk that could potentially be used as a supplement in baby formula to boost nutrition and stave off infection. If I asked you about the nutritional importance of milk, nutrients such as calcium and vitamin D might come to mind. But there is more. I began exploring novel bioactive compounds in cow’s milk in 2014, and discovered that milk contains approximately 6,000,000,000,000 natural nanoparticles called “exosomes,” per fluid ounce. When you drink milk, milk exosomes enter your body and deliver a variety of proteins, lipids, RNA, and DNA to the liver, brain, placenta, and gut. Exosomes and their cargo work their magic and support essential functions such as learning and memory, the immune system, and reproduction.

Codiak Collaborates with Ragon Institute (MGH, MIT, Harvard) to Evaluate Codiak’s exoVACC™ Vaccine Platform in SARS-CoV-2 & HIV; Combined Expertise in Engineered Exosomes and Antigen Prediction Could Drive New Approach to Vaccine Development

On June 1, 2020, Codiak BioSciences, Inc., a company at the forefront of advancing engineered exosomes as a new class of biologic medicines, announced that it has entered into two strategic collaborations with the Ragon Institute of Massachusetts General Hospital (MGH), MIT, and Harvard to investigate the potential of its exoVACC vaccine platform in (1) SARS-CoV-2, the virus that causes COVID-19, and in (2) human immunodeficiency virus (HIV). As part of the sponsored collaboration research agreements, Codiak researchers will work with Bruce Walker, MD, and Gaurav Gaiha, MD, DPhil, of the Ragon Institute to build integrated exosome-based vaccines aimed at inducing broad neutralizing antibody and antigen-specific T cell protection against the viruses. “Drs. Walker and Gaiha are luminaries in antiviral vaccine research. We are honored to collaborate to combine exoVACC with their T cell antigen prediction algorithm and biological assays in an attempt to tackle some of society’s most pressing diseases,” said Douglas E. Williams, PhD, President and Chief Executive Officer of Codiak BioSciences. “ExoVACC allows us to deliver multiple complex antigens and adjuvants, activating the key arms of the immune system to produce comprehensive immunity against the virus, similar to patients who recover from the infection. Specifically, the ability to target immune responses to the lung and other mucosal surfaces where infection occurs could represent an advance in the fight against SARS-CoV-2 and future SARS coronaviruses.” exoVACC is Codiak’s proprietary and modular vaccine system that utilizes the unique properties of exosomes to deliver antigens and adjuvants simultaneously and selectively to the same antigen-presenting cells (APCs), driving an integrated innate, cellular, and antibody-mediated immune response.