Brain Barriers
Tuesday, October 25, 2011
Presented By
The barriers of the brain play a critical role in protecting the brain from toxic and infectious agents while maintaining the ionic and volumetric environments. However, the Blood-Brain Barrier and Blood-Cerebrospinal Fluid Barrier can also create an obstacle to effective drug delivery. This symposium will review the recent advances regarding the biology and therapeutic exploitation of these two barrier systems. The first portion will deal with the unique biological properties of these barriers in health and disease, specifically covering gene expression of the endothelium and its regulation by glia. The second portion will concentrate on novel approaches to drug delivery across the barriers and focus on brain penetration of large molecules, advances in nanoparticles and adenoviral vectors, and the emerging use of ultrasound. All together, these presentations will highlight fundamentals of the brain barriers and elaborate several key approaches for therapeutically breaching these barriers.
Call for Poster Abstracts
The deadline for abstract submission has been extended to Friday, October 14, 2011. For complete abstract instructions, please send an e-mail to BrainBarriers@nyas.org with the words "Abstract Information" in the subject line. There is no need to type a message: instructions will be forwarded automatically. For questions, please call 212.298.8611.
Registration Pricing
| Member | $25 |
| Student / Postdoc / Fellow Member | $10 |
| Student / Postdoc / Fellow Nonmember | $40 |
| Nonmember Academic | $60 |
| Nonmember Not for Profit | $60 |
| Nonmember Corporate | $80 |
Presented by
Image credit: The Blood-Brain Barrier Laboratory, University of Connecticut Health Center
Agenda
* Presentation times are subject to change.
Tuesday, October 25, 2011 | |
9:00 – 9:10 AM | Introduction |
9:10 – 9:55 AM | What and Where Is the Blood–Brain Barrier? |
9:50 – 10:30 AM | The BBB in Neurological Diseases: Clinical Relevance of Available Models |
10:30 – 11:00 AM | Coffee Break |
11:00 – 11:40 AM | Blood–Brain versus Blood–CSF Barrier: Anatomical and Functional Differences and Their Pathophysiological Implications |
11:40 AM – 12:30 PM | Keynote Presentation |
12:30 – 1:30 PM | Lunch Break and Poster Session |
1:30 – 2:10 PM | Ultrasound-induced Blood–Brain Barrier Opening |
2:10 – 2:50 PM | Gene Delivery Across the Blood Brain Barrier for Treating Neurological Disorders |
2:50 – 3:20 PM | Coffee Break |
3:20 – 4:00 PM | Intranasal Insulin, Small Molecules, Biopharmaceuticals and Stem Cells Bypass the Blood-Brain Barrier to Treat Alzheimer’s, Stroke, Brain Tumors, Parkinson’s and Other CNS Disorders |
4:00 – 4:30 PM | Panel Discussion |
4:30 – 4:50 PM | Presentations by Winning Poster Presenters |
4:50 – 5:00 PM | Closing Remarks |
5:00 – 6:00 PM | Networking Reception |
Speakers
Organizers
Jo Ann Dumin, PhD
Satori Pharmaceuticals
Jo Ann earned a B.S. in Biology from Rensselaer Polytechnic Institute. Her graduate work was performed at Albany Medical College where she obtained a M.S.and Ph.D. in Biochemistry and Molecular Biology under the guidance of John Jeffrey. Jo Ann then performed a Postdoctoral Fellowship with William C. Parks at Washington University in St. Louis where she focused her research on the role of cytokines, integrins, matrix and matrix metalloprotienases in tissue repair. In March of 2000, Jo Ann joined the Inflammation Department at Warner Lambert Parke-Davis in Ann Arbor Michigan as a Principal Scientist. Warner Lambert was merged with Pfizer later that year. In 2005, Jo Ann was moved to the newly formed Dermatology Department (Anaderm) to run a laboratory focused on the development of in vivo pharmacology models and biomarker identification. During this time she was promoted to a Senior Principal Scientist. Upon the closure of the Ann Arbor site in 2007, Jo Ann obtained a position in the Groton Neuroscience Department. During her tenure, Jo Ann’slab support biomarkerdevelopment for Alzheimer’s Disease, Neuroinflammation target identification and assessed technologies which may increase the ability of therapeutics to cross the blood brain barrier. Jo Ann has significant expertise in inflammation, aging and tissue repair mechanisms in disease states. She has been involved in a wide range of projects for bothsmall molecule andbiotherapeutics as well as indication discovery efforts.
She is currently working part-time at Satori Pharmaceuticals which is developing a small molecule inhibitor for the treatment of Alzheimer’s Disease.
Mercedes Beyna, MS
Pfizer Global Research and Development
Mercedes Beyna is currently a research scientist at Pfizer, where she is using molecular, cellular, genetic, and imaging approaches in the quest to understand the biology underlying autism spectrum disorders. She is passionate about neuroscience and has worked in the field for over 10 years, in both academic and industrial laboratory settings. Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from New York University. As an active member of the Biochemical Pharmacology Discussion Group, she enjoys developing interesting and educational symposia.
Joel Pachter, PhD
University of Connecticut Health Center
Jennifer Henry, PhD
The New York Academy of Sciences
Speakers
David Begley, PhD
King's College London
David J. Begley, PhD is Senior Lecturer in Physiology at Kings College London. He heads a laboratory in the Pharmaceutical Sciences Division at Kings College investigating the blood–brain barrier and drug delivery to the CNS with a special emphasis on lysosomal storage diseases. He is author of more than sixty key peer-reviewed papers on blood–brain barrier (BBB) function and drug delivery to the CNS and has contributed more than sixteen chapters on blood–brain barrier and CNS drug delivery to edited volumes. Dr. Begley was the Friedrich Mertz Stiftungsgast professor, Johann Wolfgang Goethe-Universität, Frankfurt for the academic year 1997–1998, shortly after his collaboration with Jörg Kreuter began, and was sabbatical visiting Academic in Residence, GlaxoSmithKline 2005–2007. He was Organiser and Chairman of the Gordon Conference on "Barriers of the CNS" held in New Hampshire in 2002. He lectures frequently worldwide on the blood–brain barrier and receives research support from National Research Councils, the Pharmaceutical Industry and Charitable Foundations. He has recently created, with Prof. Maurizio Scarpa of the University of Padua, Italy, "The Brains for Brain Research Foundation," a European Task Force dedicated to the study and treatment of Neurodegenerative Lysosomal Storage Diseases. (www.brains4brain.eu)
Adam Chodobski, PhD
The Warren Alpert Medical School of Brown University
Dr. Chodobski is Associate Professor and Director of Neurotrauma and Brain Barriers Research Laboratory in the Department of Emergency Medicine. Native of Poland, he received his Master's Degree in Biomedical Engineering from the Technical University in Warsaw in 1978 and a PhD degree in Neuroscience from the Medical School of Warsaw in 1986. Dr. Chodobski joined the faculty at Alpert Medical School of Brown University in 1995. He is a member of editorial boards of Fluids and Barriers of the CNS and Neuroendocrinology. In 1999 Dr. Chodobski and his wife Dr. Joanna Szmydynger-Chodobska established a new series of Gordon Research Conferences on Barriers of the CNS. His scientific interest is in translational research related to the effects of traumatic brain injury on function of brain barriers and the role of brain barriers in the brain inflammatory response to injury.
William H. Frey II, PhD
HealthPartners Alzheimer's Research Center
Dr. William H. Frey II is Director of the Alzheimer's Research Center at Regions Hospital in St. Paul, MN, Professor of Pharmaceutics and faculty member in Neurology, Oral Biology and Neuroscience at the University of Minnesota and consultant to the pharmaceutical and biotechnology industry. His patents, owned by Novartis, Stanford University, HealthPartners Research Foundation and others, target noninvasive delivery of therapeutic agents, including stem cells, to the brain and spinal cord for treating neurological disorders, psychiatric disorders and obesity. Dr. Frey's non-invasive intranasal method for bypassing the blood-brain barrier to target CNS therapeutic agents to the brain while reducing systemic exposure and unwanted side effects has captured the interest of both pharmaceutical companies and neuroscientists. The intranasal insulin treatment he developed for Alzheimer’s disease has been shown in clinical trials to improve memory in both Alzheimer’s patients and normal adults. With over 100 publications in scientific and medical journals, Dr. Frey has been interviewed on Good Morning America, The Today Show, 20/20, All Things Considered and numerous other television and radio shows in the U.S., Europe and Asia. Articles about Dr. Frey's research have appeared in the Wall Street Journal, The New York Times, U.S. News and World Report and other magazines and newspapers around the world. Dr. Frey earned his BA in Chemistry at Washington University in 1969 and Ph.D. in Biochemistry at Case Western Reserve University in 1975.
Damir Janigro, PhD
Cleveland Clinic
Dr. Damir Janigro is a Professor of Molecular Medicine and since 1999 Director of Cerebrovascular research at the Cleveland Clinic. He was born in Croatia but received most of his high education in Milan, Italy where he obtained a PhD in Physiology and Biophysics in 1982. After post-doctoral training at Karolinska and University of Washington in Seattle, he became Assistant professor of Neurological Surgery in 1989. He remained at the University of Washington as Associate Professor until 1999. Dr. Janigro has served as Chairman for the Brain 1 study sections of the American Heart Association, as chair of the Department of Defense Epilepsy panel, and has been a permanent member of two NIH reviewing panels. He has organized several international meetings and is currently an associated editor for Epilepsia and Epilepsy currents. He received numerous multiyear NIH grants which led to the discovery of patented technologies in the field of blood–brain barrier research. He has also received funding from the Department of Energy and private companies in the US or abroad. He consulted several drug development programs, as well as the Seattle Neuroscience Foundation and the Seattle Neuroscience Institute. He has been a member of many think-tank panels focusing of neurological diseases and their treatment.
Brian Kaspar, PhD
Research Institute at Nationwide Children's Hospital
Brian K. Kaspar, PhD is Associate Professor and Principal Investigator at The Ohio State University and The Research Institute at Nationwide Children's Hospital in Columbus, Ohio. His graduate education was at University of California San Diego specializing in molecular pathology. After graduate study, he performed post-graduate work at The Salk Institute for Biological Studies in La Jolla, CA in the laboratory of Dr. Fred H. Gage where he pioneered various methodologies in viral gene transfer for neurological disorders. After finishing his training in 2004, he moved to The Ohio State/Nationwide Children's to start a laboratory focused on understanding and developing treatments for severe neuromuscular disorders. In 2009, Dr. Kaspar's group identified the first viral vector capable of traversing the blood brain barrier and utilized these findings to treat various neurological disorders, resulting in a number of high impact publications. Dr. Kaspar serves as an Editor for the journal Molecular Therapy.
Elisa Konofagou, PhD
Columbia University
Elisa Konofagou is currently an Associate Professor of Biomedical Engineering and Radiology, and Director of the Ultrasound and Elasticity Imaging Laboratory at Columbia University, New York, USA. She is also a member of the IEEE in Engineering in Medicine and Biology, IEEE in Ultrasonics, Ferroelectrics and Frequency Control, the Acoustical Society of America and the American Institute of Ultrasound in Medicine. Her main interests are in the development of novel elasticity imaging techniques and therapeutic ultrasound methods and more notably, myocardial elastography, electromechanical and pulse wave imaging, harmonic motion imaging and focused ultrasound therapy and drug delivery in the brain, with several clinical collaborations in the Columbia Presbyterian Medical Center and elsewhere. She is author of over 120 published articles in the aforementioned fields. Prof. Konofagou is also a technical committee member of the Acoustical Society of America, the International Society of Therapeutic Ultrasound, the IEEE Engineering in Medicine and Biology conference (EMBC), the IEEE International Ultrasonics Symposium and the American Association of Physicists in Medicine (AAPM) as well as a former technical standards committee member of the American Institute of Ultrasound in Medicine. Elisa serves as an Associate Editor in the Medical Physics Journal and is recipient of awards from the American Heart Association, the Acoustical Society of America, the American Institute of Ultrasound in Medicine, the Wallace H. Coulter foundation, the National Institutes of Health, the National Science Foundation and the Radiological Society of North America.
Joel Pachter, PhD
University of Connecticut Health Center
Dr. Pachter trained initially at the Mario Negri Institute for Pharmacological Research, in Milan, Italy, before pursuing his PhD studies in axonal transport in the Department of Pharmacology at The New York University School of Medicine. After obtaining his PhD, Dr. Pachter completed a NIH-sponsored postdoctoral fellowship in the Department of Physiological Chemistry at The Johns Hopkins University School of Medicine, studying the mechanisms of tubulin gene autoregulation. He then accepted a faculty position in the Department of Physiology (now Cell Biology) at the University of Connecticut Health Center, where he has remained and was promoted to Full Professor in 2003. Dr. Pachter's major research interests are the blood–brain barrier and neuroinflammation. Most recently, he has turned his attention toward the emerging technique of laser capture microdissection, applying this toward exploring gene regulation along the neurovascular unit in situ. Dr. Pachter is on the editorial board of Microvascular Research, and has (and continues to) sit on study sections at the NIH and National Multiple Sclerosis Society.
Sponsors
For sponsorship opportunities please contact Carmen McCaffery at cmccaffery@nyas.org or 212.298.8642.
Academy Friend
Grant Support
Supported by educational grants from Biogen Idec and Genentech, Inc.
Promotional Partners
Journal of Experimental Medicine (Rockefeller University Press)
International Brain Barriers Society
Abstracts
What and Where Is the Blood–Brain Barrier?
Joel Pachter, PhD, University of Connecticut Health Center
The theoretical concept of the blood–brain barrier (BBB) is now over one hundred years old. But while it is understood that the BBB strictly regulates the flux of soluble substances between the blood and the central nervous system (CNS), the full nature of the BBB still awaits description. In this regard, the microvascular endothelium is widely considered to be the anatomical substrate of the BBB, expressing tight junctions to restrict paracellular flow, and membrane transporters and cytoplasmic enzymes to modulate transcellular traffic of solutes into and out of the CNS. However, what of means to limit the traffic of cells; is this also a province of the BBB? If so, are there specific anatomic domains along the CNS microvascular tree that are responsible for different BBB properties?
Increasing awareness that the microvascular endothelium is highly heterogeneous suggests a division of labor exists at the endothelial level, and that this might dictate the specialized activities of the BBB. Arterioles, capillaries and venules make up the microvascular tree, and it has long been known that these tributaries each perform specific functions in the peripheral circulation. Now, new evidence intimates that they also may be responsible for specialized attributes of the BBB. Further research in this area will enable more accurate modeling of the BBB and highlight means by which it might be therapeutically manipulated.
The BBB in Neurological Diseases: Clinical Relevance of Available Models
Damir Janigro, PhD, Cleveland Clinic
This presentation will attempt to summarize the pharmacological and neuropathological aspects of BBB research, while at the same time providing insights into the models and experiments used in clinical subjects, animal models and in vitro. There are several aspects of BBB research that have translational and clinical relevance. The first acknowledged pathological role of the BBB was its unflattering role in multiple drug resistance. Drug resistance was and remains an unmet challenge for diseases as broad as brain neoplasms, depression and epilepsy. In vitro and animal models have proven useful yet ultimately insufficient to recapitulate clinical reality and a novel “ex situ” approach has been developed to study drug penetration in human brain. The management of drug resistance to chemotherapy has been facilitated by aggressive approaches such as the osmotic disruption of the BBB. Regardless of the merits of this procedure, its implementation demonstrated for the first time the huge clinical impact of even the most transient blood-brain barrier disruption. In fact, when the BBB was breached patients or animals experienced acute seizures, suggesting that seizure disorders may be due to a “BBB disease”. Further experiments revealed a surprising role for leukocytes in ictogenesis which in turn formed the basis of a mini-trial aimed at treating seizures with anti-inflammatory drugs.
The Blood–Brain versus Blood–CSF Barrier: Anatomical and Functional Differences and their Pathophysiological Implications
Adam Chodobski, PhD, The Warren Alpert Medical School of Brown University
The blood-cerebrospinal fluid (CSF) barrier (BCSFB) primarily resides in the choroid plexus, a highly vascularized tissue known for its ability to produce CSF. Unlike the cerebrovascular endothelium which constitutes the blood–brain barrier (BBB), the endothelium of choroidal microvessels is fenestrated, but is enclosed by a single layer of cuboidal epithelial cells connected by tight junctions that form the BCSFB. The fenestrated phenotype of choroidal endothelium facilitates the penetration of blood-borne molecules across the walls of choroidal microvessels; however, the movement of hydrophilic molecules between the vascular and the CSF compartments is impeded by tight junction complexes whose protein composition is largely similar, yet distinct from that found in the BBB. This allows for selective uptake or extrusion of endogenous molecules or xenobiotics across the BCSFB in a manner similar to that found at the BBB, although noticeable differences in expression of various transporters occur between the two barriers. The surface area of the choroidal epithelium facing the CSF is comparable to that found for the BBB, which is a significant factor in the BCSFB-mediated removal of CSF-borne drugs and/or drug metabolites. In fact, these two barriers can frequently complement each other in their ability to eliminate xenobiotics from the CNS. In addition to their transport capabilities, both the brain endothelium and choroidal epithelium can produce a variety of polypeptides, and it is becoming increasingly recognized that not only the BBB, but also the BCSFB plays an important role in neuroinflammation. This suggests that both barriers may represent attractive targets for therapeutic intervention.
Drug Delivery to the Brain: The Case for Transcytosis
David J Begley, PhD, Kings College London, London, United Kingdom
Drug penetration into the central nervous system (CNS) is severely limited by the presence of the blood–brain barrier (BBB). The BBB is formed by the endothelial cells of the capillaries in brain tissue and also by the epithelial cells of the choroid plexuses, which constitute the blood-cerebrospinal fluid barrier (BSCFB). At both barriers the endothelial and epithelial cells respectively form tight junctions between the cell boundaries which abolishes any aqueous paracellular diffusive pathway between the cells; a pathway which exists in the capillaries of most other tissues. Thus transport of solutes in and out of the brain has to be transcellular across the endothelial cells of the BBB and the epithelial cells of the BSCFB. Solutes may move into the brain passively down a concentration gradient if they are sufficiently lipid soluble to dissolve in the cell membrane, or if polar, such as glucose, amino acids and other essential nutrients they will require the presence of specific transport systems embedded in the cell membranes. Some lipid soluble molecules are actively effluxed from the barriers by ATP-binding cassette (ABC) transporters which transport these solutes out of the brain. Therapeutic drugs entering the CNS are also subject to these processes and the presence of the BBB is a major hurdle to the treatment of most CNS disease.
This presentation will focus on transctosis at the BBB, both receptor and absorbtive-mediated, and will discuss the scope for macromolecule and drug/therapeutic vector transfer to the brain.
Ultrasound-Induced Blood-Brain Barrier Opening
Elisa Konofagou, PhD, Columbia University
Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, remains a unique technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this presentation is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD) in both mice and non-human primates, and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It will be shown that the BBB can be disrupted safely and transiently under specific acoustic (pressures under 0.45 MPa) and microbubble (diameter under 8 μm) conditions. The permeability of the BBB has been measured to increase by at least two orders of magnitude while closing is highly dependent on the pressure amplitude and microbubble diameter used and can vary between 3 hours and 5 days. Finally, delivery of different molecular weights and constituency including therapeutic compounds through the opened blood-brain barrier will be shown with specific examples and evidence of neuronal uptake.
Keywords: Blood-brain barrier; brain drug delivery; disruption; focused ultrasound; microbubble; opening; safety.
Gene Delivery Across the Blood–Brain Barrier for Treating Neurological Disorders
Brian Kaspar, PhD, Research Institute at Nationwide Children's Hospital
The blood–brain barrier (BBB) acts as a protective barrier for the central nervous system (CNS) by helping to maintain appropriate concentration gradients and acting as a defense shield against pathogens. In serving this vital role, the BBB denies most systemically administered molecules entry to the CNS. Therein lays the problem in treating CNS disorders, delivery. Therapeutic drug delivery is a common problem shared by both pharmacologists and gene therapists, but the field of viral gene delivery to the CNS has recently demonstrated the remarkable ability for adeno-associated virus 9 (AAV9) to traverse the BBB when given as an intravenous (IV) infusion in both neonate and adult animals, now reported by multiple groups. We have utilized this breakthrough to treat neurological disorders using models of spinal muscular atrophy and amyotrophic lateral sclerosis. Additionally, we have examined the translation of these findings in larger species and will report on the potential for AAV9 to target the brain and spinal cord in non-human primates at various ages. Furthermore, key safety studies have demonstrated that systemically delivered virus is safe and well tolerated. In this presentation, we will demonstrate the ability to non-invasively deliver a product through the blood stream to target the brain and spinal cord, opening a plethora of basic research and therapeutic opportunities.
Intranasal Insulin, Small Molecules, Biopharmaceuticals and Stem Cells Bypass the Blood-Brain Barrier to Treat Alzheimer’s, Stroke, Brain Tumors, Parkinson’s and Other CNS Disorders
William H. Frey II, PhD, Alzheimer's Research Center
Intranasal delivery provides a practical, noninvasive, method of bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord [Dhuria et al. (2010) J Pharm Sci 99(4): 1654-1673]. This method allows drugs that do not cross the blood-brain barrier to be delivered to the central nervous system (CNS) within minutes. It also directly targets drugs that do cross the blood-brain barrier to the CNS, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. This is possible because of the unique connection that the olfactory and trigeminal nerves provide between the brain and external environment. Intranasal delivery does not require any modification of therapeutic agents. A wide variety of therapeutics, including small molecules, macromolecules and stem cells are rapidly delivered intranasally to the brain.
Using this intranasal delivery method, which I first introduced in 1989, both the treatment of and protection against stroke in animals have been demonstrated with IGF-I, deferoxamine and erythropoietin. Intranasal FGF-2 and EGF stimulate neurogenesis in the brains of adult animals, and intranasal GRN163 doubles the lifespan of animals with brain tumors, etc.
Intranasal insulin treatment, which I first developed in 1989, has been reported to improve memory and mood in healthy adults and improve memory, attention and functioning in patients with Alzheimer's disease without altering blood levels of insulin or glucose. This is not surprising as Alzheimer's patients have a brain deficiency of insulin, and without insulin, key brain areas are starved for energy and degenerate.
My colleagues in Germany and I have shown that intranasal stem cells bypass the blood-brain barrier by migrating from the nasal mucosa through the cribriform plate along the olfactory neural pathway into the brain and spinal cord. Using intranasal bone marrow-derived stem cells, we have shown major improvement in Parkinson’s while others have reported improvement in neonatal ischemia in animal models. Intranasal delivery is changing the way we treat CNS disorders.
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