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Tiny Exosomes Show Huge Potential in Clinical Medicine; ASEMV Holds Annual Meeting

Over two hundred visionary scientists, pragmatic physicians, and savvy biotech sales reps from the United States and around the world gathered from October 10-13, 2014, to discuss the latest advances in research and technology related to exosomes, a new and extremely hot area of science with possibly huge potential for game-changing applications in clinical medicine. The occasion was the fourth annual meeting of the American Society for Exosomes and Microvesicles (ASEMV). The site was the magnificently beautiful Asilomar Conference Grounds bordering the Pacific Ocean on Northern California’s Monterey Peninsula. This meeting was organized by Stephen Gould, M.D., President of the ASEMV, Professor of Biological Chemistry at The Johns Hopkins University School of Medicine, and an expert on exosome biogenesis; and by Douglas Taylor, Ph.D., Secretary-General of the ASEMV, formerly a professor at the University of Louisville, an exosome pioneer, and now the chief scientific officer (CSO) of a year-old start-up company called Exosome Sciences, Inc., located just outside Princeton, New Jersey, and a majority-owned subsidiary of Aethlon Medical, Inc. There was also notable organizational assistance from Sasha Vlassov, Ph.D., from Life Technologies (Thermo Fisher Scientific, Inc.), from Travis Antes of System Biosciences, Inc. (SBI), and from many of the graduate students in Dr. Gould’s lab. The meeting, which was described as “awesome” by more than one attendee, included 70 oral presentations and 80 posters on a very wide range of exosome-related topics, including the production of exosomes by cancer cells and the potential use of exosome molecular contents as easily accessible biomarkers for diagnosing and monitoring the course and treatment response of cancers and many other diseases and conditions, including Dengue fever, Crohn’s disease, heart damage, tuberculosis, neurodegenerative diseases such as Alzheimer’s, and prion-caused diseases such as Creutzfeldt-Jakob disease. There was also much discussion of the various technologies—either already being used, currently in development, or now being suggested as improvements—that can be used to isolate and characterize exosomes, and to also analyze their diverse molecular cargo. In addition, there was significant emphasis on the urgent need to standardize these methods so that results can be readily compared among laboratories. There were booth exhibits by a number of biotechn companies and suppliers who are marketing materials to the new and exploding market of exosome research. The exhibitors, as well as other conference supporters, included System Biosciences, Inc. (SBI), headquartered in Mountain View, CA; Maverix Biomics, headquartered in San Mateo, CA; JSR Micro Life Sciences Materials Innovation, headquartered in Sunnyvale, CA; QIAGEN, headquartered in the Netherlands, with offices in Redwood City, CA, and around the world; Life Technologies (A Thermo Fisher Scientific Brand), headquartered in Carlsbad, CA; Exosome Diagnostics, Inc., headqurtered in Cambridge, MA; Malvern Instruments, headquartered in Worcestershire, UK; iZON Sciences Ltd., headquartered in Oxford, UK; CARIS Life Sciences, headquartered in Dallas-Fort Worth, TX; Particle Metrix, headquartered in Germany; HansaBioMed, headquartered in Tallinn, Estonia; PMDx (Precision Molecular Diagnostics) at the Moffitt Cancer Center in Tampa, FL; AG Scientific, headquartered in San Diego, CA; UNIFlow™ by UNIConnect, headquartered in Salt Lake City, Utah; and Cedarlane Corporation, with main offices in Burlington-Ontario, Canada, and Burlington, NC. In addition to attendees from nearby Stanford, UCSF, and UC-Berkeley, as well as other California institutions and companies, scientists and physicians came from all over the United States and world. There were speakers and attendees from such far-off climes as New Zealand, Thailand, South Korea, Japan, Brazil, Switzerland, Germany, UK, and Finland. There were also two current US residents who came originally from Saudi Arabia and from southern Siberia (the warm part), respectively. Exosomes are tiny, subcellular, membrane-bound vesicles (approximately 30-100 nm in diameter) that are released by a wide variety of cell types and cancer cells and that can carry membrane and cellular proteins, as well as DNA, and various types of RNA, including mRNAand microRNA (miRNA), that are representative of the cell of origin. It is thought that exosomes may serve the purpose of shuttling information from one cell to another. For instance, it has been shown that exosomes can carry molecules from cancer cells that act to suppress the immune system and stimulate angiogenesis, thus encouraging cancer growth. It is believed that profiles of the various biomolecules in exosomes may serve as useful biomarkers for cancers and other diseases. High-quality RNA, and even DNA, can be isolated from exosomes and profiles of these molecules can be determined. Exosomes are shed into biofluids by cells under both normal and pathological conditions. In pathological conditions, exosomes constitute a highly enriched, intact source of disease-specific nucleic acids and proteins. In cancer, it has been shown that exosomes are shed at a much increased rate relative to the shedding rate observed for normal, healthy cells. Exosomes can be isolated from bodily fluids by ultracentrifugation and filtration, as well as by other approaches, and they offer a very attractive alternative to invasive biopsy for the diagnosis and monitoring of disease. They are said to represent the opportunity for the holy grail of the non-invasive “liquid biopsy.” While representative of the cell of origin, the cargo of exosomes contains certain molecules that are over-represented or under-represented when compared to the content of the originating cell. Consequently, it is believed that selective packaging mechanisms are involved in the loading of exosomes, but the nature of such mechanisms has yet to be elucidated. It has been suggested that it may be based, in part, on RNA “zip codes,” that are used by the cell to actively place RNAs in their proper positions in the cell, but this hypothesis is still under investigation. A number of commercial companies, such as Exosome Diagnostics and Exosome Sciences for example, are now pursuing the development of diagnostic and disease-monitoring tools for cancer and other diseases that will make use of biomarkers found in exosomes. There is also significant potential for using exosome depletion as a way of treating disease—for example, cancer-generated exosomes can inhibit the immune response and stimulate angiogenesis—if these exosomes are removed, tumor growth might be inhibited and a window of opportunity for the effective use of other anti-cancer agents might be created. In addition, there is potential for exosomes to be used as targeted delivery vehicles of therapeutic molecules to cancer cells—e.g., delivering small interfering RNA (siRNA), also called silencing RNA, specific for a particular oncogene expressed in the cancer cell. There is significant interest by pharmaceutical companies in the development of such approaches. Among the many, many exciting oral presentations at the ASEMV 2014 meeting were three particularly riveting presentations. One was delivered by Eduardo Marban, M.D., Ph.D., Director of the Cedars-Sinai Heart Institute in Los Angeles, who described experiments indicating that exosomes from cardiosphere-derived cells (CDCs) could be used to both decrease the scarring seen in myocardial infarctions (MIs) and to increase the formation of viable heart tissue after MIs. The doctor noted that an axiom in cardiology is that the scarring seen in MIs never goes away and the tissue that is lost is never regenerated. CDC-derived exosomes, however, have the potential to shatter this dogma and provide immense benefit to those who suffer MIs, an estimated 1.1 million people in the U.S. each year, for example. Dr. Marban is eager to move CDC-derived exosomes and their contents into clinical trials for the treatment of damage from MIs as soon as possible. He also believes that these exosomes and their contents may have non-ischemic cardiac applications in scleroderma and amyotropic lateral sclerosis (ALS). Previously, Dr. Marbán designed and completed the first-in-human NIH-funded CADUCEUS trial. This study was the first to show that cell therapy can repair "irreversible" tissue damage caused by heart attacks. Dr. Marban’s discoveries regarding allogeneic heart stem cells have led to a new clinical trial, ALLSTAR, now in phase 2 and being run by Capricor Therapeutics, a California-based biotechnology company. Dr. Marban counts the NIH and the California Institute for Regenerative Medicine, headquartered in San Francisco, CA, among the supporters of his work. Very intriguingly, David Wong, Doctor of Dental Medicine, Doctor of Medical Science, Director of the UCLA Center for Oral/Head & Neck Oncology Research, and Professor at the UCLA School of Dentistry, presented evidence that exosomes released from pancreatic cancer cells actually traveled to the salivary glands, whence they could be swallowed and quite possibly travel to the small intestine to interact with an immune system control center consisting of the Peyer’s patches and other immune cells in order to suppress the immune response and thus enhance the survival of the pancreatic tumor. More generally, Dr. Wong believes that exosomes secreted from the salivary glands might be used as readily accessible biomarkers for a wide range of diseases. In the CARIS Discovery Lecture, sponsored by CARIS Life Sciences and delivered early in the ASEMV meeting, Gavin Wright, Ph.D., of the Wellcome Trust Sanger Institute in the UK, presented dramatically exciting new work describing the discovery of the two proteins—one from the sperm and one from the egg—that bind to each other to launch the process that creates a membrane block to polyspermy, i.e., the fertilization of the egg by more than one sperm. The protein from the sperm is called izumo1 (from the Japanese word for marriage shrine) and the protein from the egg was identified as folate receptor 4 (Folr4). This name was changed to “Juno” in light of the fact that Folr4 does not, in fact, bind folate. Rather amazingly, prior to the landmark work of the Sanger Institute team, no receptor-ligand pair for egg fertilization had ever been identified. Dr. Wright also showed that the Juno protein from the egg is packaged and released in exosomes after fertilization and these exosome might serve as a “decoy eggs” to divert other sperm from going to the fertilized egg. He suggested that this exosome-based system might well have applications in fertility treatments and contraception. There were many other exciting presentations and posters delivered at this jam-packed, four-day conference and a more detailed description of the science discussed will be provided in an upcoming article to that will also be posted in BioQuick Online News. If you are interested in being notified when this more detailed article is published, please send your email address to logophile2000@yahoo.com (Mike O’Neill, the editor & publisher of BioQuick. BioQuick covers significant advances in life science around the globe. This premier online publication has readers in over 160 countries and includes a Japanese-language edition. BioQuick Online News has won a number of publication excellence awards and currently offers over 1,900 articles that are all readily accessible by means of a powerful search engine. See reference rlated to exosomes below in October 23, 2014 Nature News. [ASEMV] [ASEMV 2014 Annual Meeting] [Nature News on exosomes]