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2020 Nobel Prize for Physiology or Medicine Awarded Jointly to Three Scientists for Discovery of Hepatitis C Virus

On October 5, 2020, it was announced that this year’s Nobel Prize in Physiology or Medicine has been awarded jointly to three scientists who have made a decisive contribution to the fight against blood-borne hepatitis, a major global health problem that causes cirrhosis and liver cancer in people around the world. Harvey J. Alter, MD, Michael Houghton, PhD, and Charles M. Rice, PhD, made seminal discoveries that led to the identification of a novel virus, Hepatitis C. Prior to their work, the discovery of the Hepatitis A and B viruses had been critical steps forward, but the majority of blood-borne hepatitis cases remained unexplained. The discovery of Hepatitis C virus revealed the cause of the remaining cases of chronic hepatitis and made possible blood tests and new medicines that have saved millions of lives. Liver inflammation, or hepatitis, a combination of the Greek words for liver and inflammation, is mainly caused by viral infections, although alcohol abuse, environmental toxins, and autoimmune disease are also important causes. In the 1940’s, it became clear that there are two main types of infectious hepatitis. The first, named hepatitis A, is transmitted by polluted water or food and generally has little long-term impact on the patient. The second type is transmitted through blood and bodily fluids and represents a much more serious threat because it can lead to a chronic condition, with the development of cirrhosis and liver cancer. This form of hepatitis is insidious, as otherwise healthy individuals can be silently infected for many years before serious complications arise. Blood-borne hepatitis is associated with significant morbidity and mortality, and causes more than a million deaths per year world-wide, thus making it a global health concern on a scale comparable to HIV-infection and tuberculosis.

Researchers Discover Rare Genetic Form of Dementia; Mutation in VCP Gene Associated with Pathologic Buildup of Tau Proteins; Results Suggest That Restoring VCP Function Might Be Helpful in Neurological Protein Aggregation Diseases Like Alzheimer’s

A new, rare genetic form of dementia has been discovered by a team of University of Pennsylvania School of Medicine (Penn Medicine) researchers. This discovery also sheds light on a new pathway that leads to protein buildup in the brain--which causes this newly discovered disease, as well as related neurodegenerative diseases like Alzheimer's Disease--that could be targeted for new therapies. The study was published online on October 1, 2020 in Science. The article is titled “Autosomal Dominant VCP Hypomorph Mutation Impairs Disaggregation of PHF-tau.” Alzheimer's disease (AD) is a neurodegenerative disease characterized by a buildup of proteins, called tau proteins, in certain parts of the brain. Following an examination of human brain tissue samples from a deceased donor with an unknown neurodegenerative disease, researchers discovered a novel mutation in the valosin-containing protein (VCP) (image) ene in the brain, a buildup of tau proteins in areas that were degenerating, and neurons with empty holes in them, called vacuoles. The team named the newly discovered disease “vacuolar tauopathy” (VT)--a neurodegenerative disease now characterized by the accumulation of neuronal vacuoles and tau protein aggregates. "Within a cell, you have proteins coming together, and you need a process to also be able to pull them apart, because otherwise everything kind of gets gummed up and doesn't work. VCP is often involved in those cases where it finds proteins in an aggregate and pulls them apart," said Edward Lee, MD, PhD, an Assistant Professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. "We think that the mutation impairs the proteins' normal ability to break aggregates apart."

Neural Stem Cell Exosomes Can Carry Protein Cargo Across Blood-Brain Barrier in Model System; Results Suggest Exosomes May Be Effective Vehicle for Moving Drugs from Blood into Brain

Researchers have shown that certain natural nanovesicles, namely exosomes derived from c17.2 neural stem cells (NSCs), can efficiently carry a protein cargo across an in vitro model of the blood-brain barrier (BBB) [the model BBB was made up of human brain microvascular endothelial cells (hCMEC/D3)]. This is particularly significant because drug delivery to the brain has, thus far, been greatly limited by the BBB, which tightly regulates the passage of molecules from blood to the brain and vice versa. The new results were published online on September 16, 2020 in the European Journal of Neuroscience (https://onlinelibrary.wiley.com/doi/full/10.1111/ejn.14974). The article is titled “Heparan Sulfate Proteoglycan‐Mediated Dynamin‐Dependent Transport of Neural Stem Cell Exosomes in an In Vitro Blood–Brain Barrier Model.” The researchers showed that the exosomes are primarily taken up in brain microvascular endothelial cells via dynamin-dependent endocytosis, while heparan sulfate proteoglycans (HSPGs) on these endothelial cells act as receptors for the exosomes. The authors suggest that their data support the development of exosomes as delivery vehicles for the treatment of brain disorders via intravenous administration, obviating the need for invasive intracerebral or intracerebroventricular administration routes. Moreover, active HSPG targeting of nanoparticles, including exosomes, may be exploited for effective crossing of the BBB. The authors of the article are Bhagyashree S. Joshi (photo), PhD candidate, and her advisor Inge S. Zuhorn, PhD, Associate Professor, from the Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, The Netherlands.

[European Journal of Neuroscience article]

Codiak Initiates Patient Dosing in Phase 1/2 Clinical Trial of exoSTING™ Exosomes for Treatment of Solid Tumors; These Exosomes Contain Proprietary Stimulator of Interferon Genes (STING) Agonist to Activate Innate Immunity in Tumor Microenvironment

On October 1, 2020, Codiak BioSciences, Inc., a clinical-stage company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, announced the initiation of patient dosing in its Phase 1/2 clinical trial of exoSTING. exoSTING is a novel exosome therapeutic candidate engineered with the company’s engEx Platform and designed to deliver Codiak’s proprietary STING (stimulator of interferon genes) agonist specifically to tumor-resident antigen-presenting cells (APCs) to locally activate the innate immune response. The trial, which will study exoSTING in solid tumors, is Codiak’s second human clinical trial and the second clinical development program the Company has initiated in the past month. “We are enormously proud to now have both of our lead candidates in the clinic, the result of years of engineering and manufacturing innovation and a significant step forward towards fulfilling our goal of pioneering the development of engineered exosomes as a new class of medicines for diseases with high unmet medical needs,” said Douglas E. Williams, PhD, CEO, Codiak. “With exoSTING, the data from our in vitro and in vivo preclinical studies support our desired product profile, demonstrating that we can achieve targeted engagement of the STING pathway to potentially overcome the lack of cell specificity, tolerability, and limited single-agent antitumor activity associated with previous STING agonists.” exoSTING is an exosome therapeutic candidate engineered with Codiak’s engEx Platform to incorporate its proprietary STING agonist inside the lumen of the exosome, while expressing high levels of the exosomal protein, PTGFRN (prostaglandin F2 receptor inhibitor) (https://en.wikipedia.org/wiki/PTGFRN), on the surface.

Cryptic Exon Discovered in Sry Gene on Y-Chromosome in Mice Is Critical for Male Sex Development; Finding May Enable Selection for the Desired Sex in Agricultural Industries Such As Dairy (Females) or Beef (Males)

An international research collaboration among researchers at the University of Queensland, Osaka University, and Tokushima University. has found that the Y-chromosome gene that makes mice male is made up of two different DNA parts, not one, as scientists had previously assumed. UQ's Institute of Molecular Biosciences Emeritus Professor Peter Koopman, PhD, said the critical DNA fragment had been hidden from researchers for more than 30 years. "Expression of the Y chromosomal gene Sry (sex-determining region Y) is required for male development in mammals and since its discovery in 1990 has been considered a one-piece gene," Dr. Koopman said. "Sry turns out to have a cryptic second part, which nobody suspected was there, that is essential for determining the sex of male mice. We have called the two-piece gene Sry-T." The scientists tested their theory and found that male mice (XY) lacking in Sry-T developed as female, while female mice (XX) carrying a Sry-T transgene developed as male. The success rate for the experiments was almost 100 per cent. The results were reported in the October 2, 2020 issue of Science. The article is titled “The Mouse Sry Locus Harbors a Cryptic Exon That Is Essential for Male Sex Determination.” Dr. Koopman said the discovery would change how basic biology and evolution is taught around the world. "For the last 30 years, we've been trying to figure out how this works," he said. "Sry is a master switch gene because it flicks the switch for male development, it gets the ball rolling for a whole series of genetic events that result in a baby being born as a male instead of female. This new piece of the gene is absolutely essential for its function; without that piece, the gene simply doesn't work.

Exosome Treatment Improves Recovery from Heart Attacks in Pig Model

Science has long known that recovery from experimental heart attacks is improved by injection of a mixture of heart muscle cells, endothelial cells, and smooth muscle cells, yet results have been limited by poor engraftment and retention, and researchers worry about potential tumorigenesis and heart arrhythmia. Now, research in pigs shows that using the exosomes naturally produced from that mixture of heart muscle cells, endothelial cells, and smooth muscle cells--which were all derived from human induced pluripotent stem cells (hiPSCs)--yields regenerative benefits equivalent to the injected human induced pluripotent stem cell-cardiac cells, or hiPSC-CCs. Exosomes are sub-cellular, cell-released, membrane-bound extracellular vesicles (EVs) that can contain biologically active proteins, RNAs, and microRNAs. Exosomes are well known to participate in cell-to-cell communication, and they are actively studied as potential clinical therapies. “The hiPSC-CC exosomes are acellular and, consequently, may enable physicians to exploit the cardioprotective and reparative properties of hiPSC-derived cells while avoiding the complexities associated with tumorigenic risks, cell storage, transportation, and immune rejection,” said Ling Gao, PhD, and Jianyi “Jay” Zhang (photo), MD, PhD, University of Alabama at Birmingham (UAB), corresponding authors of the study, published online on September 16, 2020 in Science Translational Medicine. “Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.” The article is titled “Exosomes Secreted by hiPSC-Derived Cardiac Cells Improve Recovery From Myocardial Infarction In Swine.” At UAB, Dr.

Scientists Trace 13.5% of Severe COVID-19 to Auto-Antibodies Against Type I Interferons or Mutations in Type I Interferon Genes

More than 10 percent of people who develop severe COVID-19 have misguided antibodies that attack not the virus, but the immune system itself, new research shows. Another 3.5 percent, at least, carry a specific kind of genetic mutation. In both groups, the upshot is basically the same: The patients lack type I interferons, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether the proteins have been neutralized by so-called auto-antibodies, or were not produced in sufficient amounts in the first place due to a faulty gene, their missing-in-action appears to be a common theme among a subgroup of COVID-19 sufferers whose disease has thus far been a mystery. Published online on September 24, 2020 in two papers in Science, the findings help explain why some people develop a disease much more severe than others in their age group—including, for example, individuals who required admission to the ICU despite being in their 20s and free of underlying conditions. The findings may also provide the first molecular explanation for why more men than women die from the disease. The two open-access Science articles are “Auto-Antibodies Against Type I IFNs in Patients with Life-Threatening COVID-19” (https://science.sciencemag.org/content/early/2020/09/23/science.abd4585) and “Inborn Errors of Type I IFN Immunity in Patients with Life-Threatening COVID-19” (https://science.sciencemag.org/content/early/2020/09/29/science.abd4570). “These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19,” says Jean-Laurent Casanova, MD, PhD, Head of the St.

HPV Vaccine Proves Effective in Preventing Cervical Cancer; Girls Vaccinated Before Age 17 Show 88% Reduction in Cervical Cancer; “Data Strongly Supports Continuing HPV Vaccinations of Children and Adolescents Through National Vaccination Programs"

Women vaccinated against HPV (human papilloma virus) have a significantly lower risk of developing cervical cancer, and the positive effect is most pronounced for women vaccinated at a young age. That is according to results of a large study by researchers at Karolinska Institutet in Sweden published online on September 30, 2020 in the New England Journal of Medicine. The article is titled “HPV Vaccination and Risk of Invasive Cervical Cancer." “This is the first time that we, on a population level, are able to show that HPV vaccination is protective not only against cellular changes that can be precursors to cervical cancer, but also against actual invasive cervical cancer," says Jiayao Lei (at right in photo), PhD, researcher at the Department of Medical Epidemiology and Biostatistics at Sweden’s Karolinska Institutet and the study's corresponding author. "It is something we have long suspected but that we are now able to show in a large national study linking HPV vaccination and development of cervical cancer at the individual level." HPV is a group of viruses that commonly causes genital warts and different types of cancer, including cervical cancer, a disease that globally kills more than 250,000 women a year. More than 100 countries have implemented national vaccination programs against HPV, and Sweden, as of August 2020, also includes boys in this program. Previous studies have shown that HPV vaccine protects against HVP infection, genital warts, and precancerous cervical lesions that could develop into cancer of the cervix. However, there is lack of large population-based studies that, on an individual level, have studied the link between HPV vaccine and so-called invasive cervical cancer, which is the most severe form of the disease.

Major Genetic Risk Factor for COVID-19 Inherited from Neanderthals, Study Suggests

Since first appearing in late 2019, the novel virus, SARS-CoV-2, has had a range of impacts on those it infects. Some people become severely ill with COVID-19, the disease caused by the virus, and require hospitalization, whereas others have mild symptoms or are even asymptomatic. There are several factors that influence a person's susceptibility to having a severe reaction, such as their age and the existence of other medical conditions. But one's genetics also plays a role, and, over the last few months, research by the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/) has shown that genetic variants in one region on chromosome 3 impose a larger risk. Now, a new study, published online on September 30, 2020 in Nature (https://www.nature.com/articles/s41586-020-2818-3), has revealed that this genetic region is almost identical to that of a 50,000-year old Neanderthal from southern Europe. Further analysis has shown that, through interbreeding, the variants came over to the ancestors of modern humans about 60,000 years ago. The Nature article is titled “The Major Genetic Risk Factor for Severe COVID-19 Is Inherited From Neanderthals.” "It Is Striking That The Genetic Heritage From Neanderthals has such tragic consequences during the current pandemic," said Professor Svante Pääbo, who leads the Human Evolutionary Genomics Unit (https://groups.oist.jp/heg) at the Okinawa Institute of Science and Technology Graduate University (OIST). Chromosomes are tiny structures that are found in the nucleus of cells and carry an organism's genetic material. They come in pairs with one chromosome in each pair inherited from each parent. Humans have 23 of these pairs.

Regeneron's REGN-COV2 Antibody Cocktail Reduced SARS-CoV-2 Viral Levels and Improved Symptoms in Non-Hospitalized COVID-19 Patients, Report States

On September 29, 2020, Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) announced the first data from a descriptive analysis of a seamless Phase 1/2/3 trial of its investigational antibody cocktail REGN-COV2, showing it reduced viral load and the time to alleviate symptoms in non-hospitalized patients with COVID-19. REGN-COV2 also showed positive trends in reducing medical visits. The ongoing, randomized, double-blind trial measures the effect of adding REGN-COV2 to usual standard-of-care, compared to adding placebo to standard-of-care. This trial is part of a larger program that also includes studies of REGN-COV2 for the treatment of hospitalized patients, and for prevention of infection in people who have been exposed to COVID-19 patients. "After months of incredibly hard work by our talented team, we are extremely gratified to see that Regeneron's antibody cocktail REGN-COV2 rapidly reduced viral load and associated symptoms in infected COVID-19 patients," said George D. Yancopoulos, MD, PhD, President and Chief Scientific Officer of Regeneron. "The greatest treatment benefit was in patients who had not mounted their own effective immune response, suggesting that REGN-COV2 could provide a therapeutic substitute for the naturally-occurring immune response. These patients were less likely to clear the virus on their own, and were at greater risk for prolonged symptoms. We are highly encouraged by the robust and consistent nature of these initial data, as well as the emerging well-tolerated safety profile, and we have begun discussing our findings with regulatory authorities while continuing our ongoing trials. In addition to having positive implications for REGN-COV2 trials and those of other antibody therapies, these data also support the promise of vaccines targeting the SARS-CoV-2 spike protein."

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