Exosomes and Microvesicles
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Wednesday, September 19
» Opening Plenary Session
2:00-3:00 Main Conference Registration
3:00-3:10 Welcoming Remarks from Conference Director
Julia Boguslavsky, Executive Director, Conferences, Cambridge Healthtech Institute
3:10-3:15 Chairperson's Opening Remarks
3:15-3:45 Rules, Tools and Data Pools: The Critical Path's Recipe for Speeding Drug Development
Carolyn Compton, M.D., Ph.D., President & CEO, Critical Path Institute
Both regulatory agencies and the medical products industry recognize the need for new biomarkers and methods to speed the development and delivery of effective, safe medicines to patients. However, developing consensus on the utility of new biomarkers and establishing a process for putting them into routine practice in medical product development and regulatory decision making is a complex undertaking. In 2009 and 2010, respectively, the European Medicines Agency and the FDA released guidance that describes a voluntary pathway for "qualification" of novel drug development tools or methods. Determining the relative advantages/disadvantages and evidentiary standards required for regulatory "qualification," applying a novel biomarker on a specific drug development program, or submitting an application for a diagnostic device are challenging tasks. The Critical Path Institute (C-Path) acts as a trusted third party to lead six pre-competitive global consortia that, with the cooperation of the FDA, develop and qualify molecular and imaging biomarkers as well as patient-reported outcomes instruments for specific contexts of use in medical product development. Several C-Path consortia use Clinical Data Interchange Standards Consortium disease area data standards in constructing clinical trial databases from which disease progression models and virtual clinical trial simulations are developed. Specific examples from these consortia will be utilized to illustrate the power of pre-competitive collaboration in the generation and qualification of drug development tools.
3:45-4:15 Technology Transformation at FDA: Driving Efficiency and Unleashing Innovation
Eric D. Perakslis, Ph.D., Chief Information Officer and Chief Scientist, Informatics, U.S. Food and Drug Administration
The U.S. Food and Drug Administration has recently taken significant steps to modernize and improve its information technology and informatics capabilities. The resulting infrastructure, architecture, innovation pathways and data sharing initiatives are intended to ease regulatory burden on innovators while maintaining the highest quality standards. In this talk, Eric Perakslis, Ph.D., the Chief Information Officer and Chief Scientist for Informatics at FDA, will discuss these initiatives in detail and will provide success examples, recent progress and future directions.
4:15-4:45 Turning an Active Compound into a Personalized Medicine: Do Biomarkers Help or Hinder?
Geert Kolvenbag, M.D., Ph.D., Global Product Vice President, AstraZeneca
The co-development of drug and biomarker has several inherent risk and challenges. In addition the expectations and demands of the oncology community have increased over the last years. These challenges will be illustrated by a case study of a very active compound destined for a fast development program as a personalized medicine, but running into scientific, diagnostic and development challenges. This experience creates questions for development of drugs and diagnostics today and in the future.
4:45-5:15 Strategies to De-Risk Drug Development Utilizing Biomarkers in Early Clinical Trials
Scott Kennedy, Ph.D., Global Head, Biomarker Development, Novartis Institutes for BioMedical Research, Inc.
Other than recent examples in oncology, the emerging field of personalized medicine has yet to live up to its promise of enabling more rapid, efficient drug development and providing customized therapies to patients. This presentation will exemplify and discuss how leveraging biomarkers which inform a biological understanding of targeted and disease pathways can increase the success of early clinical development. These biologically relevant markers can also enable the identification and treatment of parallel disease populations and serve as stratification or response markers for later stage development. This presentation will also discuss several of the challenges that this paradigm presents.
5:15-5:45 Implementing a Personalized Medicine Strategy: Is There Light at the End of the Tunnel?
Jeremy Barton, M.D., Vice President, Head of Oncology Clinical Research, Pfizer
Personalized medicine, the practice of tailoring treatment to individual characteristics of the patient, has emerged as a major force in oncology in the last decade with the expectation of significant improvement in safety and efficacy of therapeutics. The ultimate success of this paradigm is dependent on a variety of factors. The choice of drug target, selection of patients by companion diagnostic, regulatory authority acceptance of novel trial designs which best serve this strategy, improved health care information technology, insurance coverage and reimbursement are just a few of the important variables in the equation. This presentation will provide an overview of the current situation and discuss factors which will impact future progress in the field.
5:45-6:45 Welcome Reception in the Exhibit Hall with Poster Viewing
Thursday, September 20
7:30-8:15 am Morning Coffee or Sponsored Breakfast Presentation (Opportunity Available)
Contact Ilana Quigley at firstname.lastname@example.org or 781-972-5457
8:30-8:55 Exosomes as Biomarkers for Translational Medicine
Holly Hilton, Ph.D., Head, Disease and Translational Genomics, F. Hoffmann-La Roche
The need for new, relevant biomarkers for translational drug discovery research is critical. Exosomes are small microvesicles secreted by a wide range of mammalian cell types under normal and pathological conditions. The unique signature of exosomal membrane and cytoplasmic proteins as well as mRNAs and miRNAs can reveal the cell of origin and the condition of those cells. Isolation and profiling of exosomes from accessible patient biofluids, such as urine, blood, BALF and CSF, make them ideal candidates as biomarkers. Examples of their utility as disease biomarkers of chronic kidney disease and Alzheimer’s as well as possible applications of patient stratification will be discussed. The current state of challenges to the widespread use of fluid-based biomarkers will be explored.
8:55-9:20 Genetic Insights into Brain Tumors Using Extracellular Vesicles in Biofluids
Xandra Breakefield, Ph.D., Professor, Neurology, Harvard Medical School; Geneticist, Molecular Neurogenetics, Massachusetts General Hospital
Glioma tumor cells release a variety of extracellular vesicles containing proteins, lipids and nucleic acids, which are representative of the tumor cells. These vesicles provide a means for the tumor to eliminate unwanted substances and also to communicate with cells in their environment. In the case of brain tumors some of these microvesicles are released into the cerebrospinal fluid (CSF) and blood. Our group has used RNA in CSF and serum microvesicles from brain tumor patients to detect mutations in EGFR and IDH1 by RT-PCR, BEAMing and deep sequencing. These serve as robust and non-invasive biomarkers for tumor status.
9:20-9:45 Clinical Utility of Exosomes as Diagnostic and Prognostic Markers in Cancer
Rachel E. Raab, M.D., Assistant Professor of Medicine, Division of Hematology/Oncology, East Carolina University Brody School of Medicine
Tumor-derived exosomes are membrane-bound, endosome-derived vesicles between 50-100 nm that bear protein signatures related to their cell of origin and contain mRNAs and microRNAs. Most cell types, including tumor cells, secrete them. Exosomes play a role in cell-cell communication and affect target cells by stimulating them directly or by transferring molecules between cells. Tumor-derived exosome analysis may be a novel diagnostic and prognostic biosignature in many solid tumors including breast cancer, ovarian cancer, colon cancer, lung cancer and prostate cancer.
9:45-10:45 Coffee Break in the Exhibit Hall with Poster Viewing
10:45-11:10 Exploring Exosomes as a Surrogate Marker for Neuroscience Clinical Research
Reyna Favis, Ph.D., Scientific Director and Head, Neuroscience Biomarkers Laboratory, Janssen Pharmaceutical Companies of Johnson & Johnson
Neurological and neuropsychiatric disease research has been hampered by the inability to perform molecular assessments of the CNS in living patients. While analyses of postmortem brain tissue and lymphocytes from living donors have been exploited in an attempt to obtain insight, both tissue types suffer from numerous caveats. Exosomes are a recognized mechanism for intercellular communication. By tapping into this cellular communication modality, we reason that it will be possible to gain insight into the activities of inaccessible tissue of the central nervous system.
11:10-11:40 Predictive Biomarkers that Reflect Cellular Decision Making: Exosomal Transcription Factors and microRNA
Peter S. T. Yuen, Ph.D., Staff Scientist, Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Proximal fluid biomarkers can add a dimension of organ specificity to complement circulating biomarkers. Exosomes represent a minor subfraction of urine that promises unique insights into kidney function, because their biogenesis preserves information content from the cytoplasm and plasma membrane from all types of epithelial cells that line the nephron. We demonstrated that exosomal transcription factors Wilms Tumor-1 (WT-1) and Activating Transcription Factor 3 (ATF3) are diagnostic biomarkers for chronic acute and kidney diseases, respectively. Further, exosomal microRNAs are diagnostic biomarkers. However, we demonstrate that these complementary biomarkers have great potential to predict the extent of injury in outbred mice with a wide range of severity.
11:40-12:05 The Majority of microRNAs Detectable in Serum & Saliva Are Concentrated in Exosomes
Alessia Gallo, Ph.D., Fellow, Molecular Physiology & Therapeutics Branch, NIDCR, National Institutes of Health
12:05-1:30 Enjoy Lunch on Your Own
1:30-1:35 Chairperson’s Opening Remarks
1:35-2:00 Characterization and Functional Analysis of Tumor-Derived Exosomes in Malignant Progression
Jacqueline Bromberg, M.D., Ph.D., Associate Member, Memorial Sloan-Kettering Cancer Center
2:00-2:25 Exosomes at the Nanoscale
Shivani Sharma, Ph.D., Project Scientist, California Nanosystems Institute, University of California, Los Angeles
The nanoscale morphological, biomechanical and surface biomolecular properties of single exosomes are critical for diagnostic applications and for developing new cell delivery systems. Due to the small size (40-100 nm), exosomes have been exclusively visualized with Transmission Electron Microscopy (TEM). Recently, Scanning Probe Microscopy has been applied to study the nanoscale characteristics of these vesicles. A new ultrasensitive low force Atomic Force Microscope (AFM) revealed sub-structural features in single human saliva exosomes. A combination of correlative Field Emission Scanning Electron Microscopy (FESEM), AFM and Super-Resolution STED Microscopy approaches to further understand the nanoscale characteristics of exosomes at the vesicular and sub-vesicular level will be discussed.
2:25-2:55 Exosome Associated Proteomic Markers for Determination of Pre-Term Birth RiskAlan M. Ezrin, Ph.D., President & CEO, NX PharmaGenCirculating placental exosomes modulate intercellular communication between the maternal immune system and the fetus, and exosome-associated protein biomarkers may be valuable determinants of pregnancy complications. Our independent, blinded studies demonstrate a high correlation of such exosomal markers (derived from maternal serum samples at week 15-17 of gestation) to preterm and term outcomes. Our verification of these statistically valued biomarkers warrants accelerated commercial development of assays for this substantial unmet need.
2:55-3:20 Identification and Proteomic Profiling of Exosomes from Urine
Mark A. Knepper, M.D., Ph.D., Chief, Epithelial Systems Biology Group, Laboratory of Kidney and Electrolyte Metabolism, National Heart Lung and Blood Institute, National Institutes of Health
Exosomes can be isolated from human urine in relatively large quantities. They are secreted by each renal epithelial cell type facing the urinary space including glomerular podocytes. Hence, they provide source material for biomarker discovery referable to a variety of renal diseases. Large-scale LC-MS/MS profiling of exosomes isolated from normal humans allowed creation of a urinary exosome database. We have developed a systems-biology based strategy for analysis of LC-MS/MS data that allows identification of biological processes perturbed in specific renal diseases, illustrating the approach in urine samples from transplant patients undergoing different forms of rejection.
3:20-4:15 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15-4:20 Chairperson’s Opening Remarks
4:20-4:45 Microvesicles in Cardiovascular Health and Disease
Muthuvel Jayachandran, Ph.D., Associate Professor, Physiology and Biomedical Engineering, College of Medicine, Mayo Clinic
Activated cells shed sealed membrane vesicles of less than 1µm in diameter called microvesicles (or microparticles). The molecular composition and number of microvesicles in the blood depend upon their cell of origin and the stimulus that triggers their generation. Thus, microvesicles may serve as novel biomarkers of ongoing disease processes before or after symptoms appear. Objectives: 1) define and differentiate micro- and nano-vesicles and their generation; 2) describe methodologies to characterize blood-borne microvesicles; 3) demonstrate the potential of microvesicles in health and disease; 4) conclude blood-borne microvesicles as novel biomarkers for diagnosis, prognosis and management of cardiovascular diseases.
4:45-5:10 Roles for Exosomes in Immune Responses to Mycobacterium tuberculosis
Pamela Wearsch, Ph.D., Assistant Professor, Pathology, Case Western Reserve University
Mycobacterium tuberculosis (Mtb) is a highly successful intracellular pathogen that infects professional APCs such as macrophages and DCs. To evade host immune responses and establish persistence, Mtb has evolved several strategies to inhibit antigen presentation and microbial clearance. To counteract immune evasion mechanisms, we propose that host cells respond by releasing exosomes. We have found that Mtb-infection of APCs induces a robust release of exosomes containing Mtb PAMPs and antigens. We propose that these shed membranes broadcast Mtb PAMPs and antigens beyond infected cells, inducing both innate and adaptive immune responses by a larger set of host cells.
5:10-5:35 Exosomes/Microvesicles and the Pathogenesis of Diabesity
Günter Müller, Ph.D., Research & Development, Diabetes Division, Obesity Strategy Team, Sanofi Pharma Germany, Frankfurt am Main
The predictive power of classical biomarkers for diabesity is currently not sufficient for individual differentiation of the pathogenesis and therapeutic options. Monitoring of multi-parameter patterns may add a novel layer of quality. Small membrane vesicles, i.e., exosomes and microvesicles (EMVs), equipped with a variety of transmembrane and glycosylphosphatidylinositol-anchored proteins, mRNAs, microRNAs and phospholipids, are known to be released from various tissues (e.g., adipose) and blood cells into plasma in differential fashion in response to normal and diabetogenic/obesogenic conditions. EMVs seem to reflect the complex patterns and their alterations in gene expression and function of those cells and tissues being involved in the pathogenesis of diabesity and thus could be useful for its prediction, diagnosis and therapy monitoring.
5:35-6:00 Exosomes as “Stress Balls”: Extracellular Vesicles Can Pass Unfolded Protein Response Phenotypes from Stressed Cells to Unstressed Cells
Michael Graner, Ph.D., Associate Professor, Neurosurgery, University of Colorado School of Medicine
Exosomes are virus-sized extracellular vesicles derived from the cellular endosomal system. Their contents reflect the nature and status of their cell of origin, and thus may be considered reflective of cellular phenotype. We show that exosomes from glioma (brain tumor) cells can passage stress phenotypes of the “unfolded protein response” (UPR) from cells undergoing that form of endoplasmic reticulum stress, to naïve, unstressed cells. This form of unconventional stress conditioning has consequences for glioma cell migration, chemoresistance, and survival, and undoubtedly plays roles in the devastating outcomes experienced by patients with high grade gliomas.
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