Brain Barriers: A Hurdle for Drug Discovery
Posted December 24, 2011
We like to think the brain is special. In fact, all the neurons and associated satellite cells throughout the mammalian central nervous system (CNS)—which includes the spinal cord—comprise a highly specialized tissue. The complex circuitry executed by the CNS requires a unique cellular environment. The circulatory system maintains the fluid bathing most bodily tissues, but the CNS inhabits its own cerebrospinal fluid (CSF). In addition, a poorly understood system of cell–cell connections defines a "blood–brain barrier" (BBB) that segregates the brain from the blood vasculature to maintain distinct local chemical conditions. BBB integrity is crucial for normal health, but it also presents a challenge to drug delivery. Although a variety of hereditary and age-related cognitive disorders, as well as certain brain cancers, may prove responsive to drug treatment, any potentially therapeutic chemical must bypass the BBB first.
The October 25, 2011, meeting of the Biochemical Pharmacology Discussion Group addressed Brain Barriers: A Hurdle for Drug Discovery and brought together biochemists, clinical pharmacologists, and industry specialists to explore current BBB research. Speakers considered the physiological nature of the BBB, emerging techniques to transiently disrupt the BBB or to allow drugs to circumvent it, and the risks associated with these techniques.
In her introductory remarks Jo Ann Dumin, an organizer of the Brain Barrier event and researcher at Satori Pharmaceuticals, highlighted the intersector nature of the field by calling for a non-competitive consortium between academia and industry to solve the BBB challenge. The nascent research presented throughout the day and the intersection of ideas born from multiple disciplines underscored her suggestion.
Joel Pachter of the University of Connecticut Health Center began by demonstrating that physiologists do not agree which level of vascular organization or subcellular structures designate the BBB. Definitions range from general, citing only endothelial cells lining blood vessels, to detailed, naming specific tight junctions that lash cells together. Pachter argued that rigorous biological knowledge of BBB construction must inform clinical work. This notion drives research in his laboratory where experimental systems have been devised to identify relevant components of the BBB. He showed that advanced fluorescent microscopy can be used to calculate the densities of tight junctions on different blood vessel surfaces. Capillaries top the list in this assay for tight junctions per unit surface area, suggesting the vessels are key to the BBB.
Pachter further explained that cultured endothelial cells derived from brain tissue and used routinely in laboratories may not accurately reflect the BBB, because the vascular population from which they originated cannot be readily defined. To get a better understanding of which vessel population(s) contribute to the BBB, he proposed using laser capture microdissection, which allows for selection of specific cells from a heterogeneous population. The technique can be used to analyze endothelia from distinct types of vessels separately, allowing for comparisons of global gene and protein expression patterns. Pachter concluded by emphasizing the perhaps underappreciated heterogeneity of endothelial tissues.
Echoing Joel Pachter's introduction, Damir Janigro of the Cleveland Clinic pointed out that even apparently trivial questions about the BBB remain unanswered. His talk pivoted around the effects of induced, and even pathological, BBB disruption. Janigro's team studies epilepsy and the associated seizures, among other neuropathological disorders. Their analyses of a rat model of epilepsy in which pilocarpine administration induces seizures revealed that the drug does not significantly penetrate the BBB under any conditions, but it does precipitate BBB disruption. Direct injection into the brain resulted in loss of consciousness without convulsions. These observations suggested that mere BBB breach may cause seizures. A battery of experiments in model organisms correlated BBB opening with seizure onset, as tracked by electroencephalography (EEG), a measure of electrical activity in the brain.
Janigro's group also tested the hypothesis in human patients undergoing clinical surgeries and found that elevated serum S100β—a molecular marker of a breached BBB—predicted seizure onset. These experiments informed clinical work by Janigro and his colleagues on certain forms of epilepsy, but the results are also pertinent to the development of intentional BBB disruption methodologies for the purposes of drug delivery. Janigro introduced the ex situ endothelial culture tubes used in his laboratory to screen for the effects of various drugs on BBB permeability. The plastic tubes are seeded with human endothelial cells and allowed to develop into "mock" blood vessels. By flowing buffer through the vessels (mimicking blood flow) the researchers can observe the effect of shear forces on endothelium, while the permeability of the cell layer serves as a bench-top model of the BBB.
The day's lectures centered on the endothelial barrier between blood and brain tissue, but Adam Chodobski from the Warren Alpert Medical School at Brown University spoke about the less appreciated blood–cerebrospinal fluid barrier (BCSFB). The BCSFB resides in the choroid plexus, a highly vascularized organ consisting of epithelial cells, which is located within the ventricles (CSF-filled cavities) of the brain and is responsible for generating CSF. Since this liquid bathes the brain and spinal cord, it too is segregated from blood. The separation is similar to but distinct from that characterizing the BBB, and therefore represents an additional facet of brain-targeted drug delivery. Chodobski pointed out that CSF, which turns over four times a day in an adult human and drains into the peripheral circulation, plays an important role in clearance of drugs from their target sites. As delivery routes, the BCSFB and CSF may be useful for targeting brain cells abutting the CSF space, but other brain regions may be too far for effective distribution of introduced chemicals.
David Begley of King's College London began by reiterating two themes that cut across all the talks. First, the endothelium of the BBB is not homogeneous; general descriptions of its molecular properties therefore fail to provide a complete picture. Second, CNS vasculature is distinct from peripheral vasculature. Specifically, peripheral capillary cells are fenestrated: not sealed together by tight junctions, which allows solutes, large molecules, and even cells to pass between them. Peripheral capillary cells also routinely transport certain molecules by engulfing them on one surface, and releasing them on the opposite surface. Current dogma holds that the BBB does not transcytose in this way, but Begley's research demonstrates otherwise. He and his collaborators observed that although receptor-mediated transcytosis across the BBB occurs relatively rarely, it nevertheless contributes non-negligibly to BBB permeability. The range of BBB-active receptors is poorly characterized, but at least some are known and appear to exhibit limited but still useful flexibility in the classes of molecules they recognize. This opened the door to a novel delivery method: nanoparticles. The engineered micron-sized beads are coated with a marker that docks to receptors mediating endocytosis. Initial trials have demonstrated that intravenously injected nanoparticles pass through the rodent BBB and end up in neuronal cytoplasm within 30 minutes. The beads degrade in the cell with time. Further pharmacological and materials science research will address precisely how the nanoparticles can serve as a platform for specific drugs.
Innovative technology also featured in the presentation by Elisa Konofagou. Her group at Columbia University experiments with focused ultrasound (FUS) as a noninvasive tool to transiently open the BBB. FUS targets brain regions selectively by disrupting only a small (mm2- to cm2-sized) defined area of the BBB, with most of the disrupting effects localized to the acoustic focus. As a high-frequency sound emitted by FUS propagates across living tissue, it imparts mechanical perturbations, which in turn generate heat. The secondary thermal effect can precipitate cell damage, but this can be minimized by an injection of microbubbles (already established and approved as safe in other applications). The microbubbles resonate with the applied FUS frequency and cause BBB opening without generating excessive heat.
MRI imaging of murine and primate brains during FUS revealed the size and duration of "passive cavitations" under various conditions, and the laboratory has honed in on a set of acoustic frequencies and microbubble sizes that generate cavities of desired area and duration. Because FUS physically breaches the BBB, it can be applied broadly to any drug that can be delivered intravenously. A graduate student in the Konofagou laboratory, Yao-Sheng Tung, presented his work on identifying the ideal microbubble size. Tung's poster received one of two prizes awarded in the symposium's poster competition.
Our molecular understanding of some CNS-associated disorders suggests that gene therapy, rather than drugs, may prove therapeutic. Gene therapy involves the targeted delivery of genetic material to cells otherwise lacking the correct genetic information. Getting genes into cells is challenging enough, but getting them past the BBB poses an even greater hurdle. Brian Kaspar of the Ohio State University and The Research Institute at Nationwide Children's Hospital studies the pathology and therapeutics of neuromuscular disorders, which often stem from problems behind the BBB. Kaspar and his colleagues have found that adeno-associated virus 9 (AAV9) can bypass the BBB. Since viruses are essentially small capsules capable of delivering genetic payloads to very specific targets, this observation opens many avenues for future research. Preliminary studies have demonstrated the feasibility and tolerability of the approach in non-human primates.
Conor P. Foley, one of two winners of the poster competition, described arterial delivery of gene therapy in mice: injection of a viral vector into a specific artery feeding only a target region of the brain, coupled with chemically-induced BBB disruption delivered high doses of the vector without the need for surgery.
William H. Frey II of the Health Partners Alzheimer's Research Center at Regions Hospital and the University of Minnesota spoke of avoiding the BBB altogether when targeting drugs to the CNS. Extracellular pathways connect the nasal passage essentially directly to the brain cavity in the region where olfactory nerves communicate between the two compartments. Intranasal delivery is therefore noninvasive, amenable to a wide range of chemical compounds, and functional with low drug doses. An interest in low glucose uptake by brain tissue in Alzheimer's patients led Frey and his colleagues to successfully demonstrate the effectiveness of intranasally administered insulin. More recently, intranasally administered stem cells in a rat model of neurodegenerative disease were shown to migrate into the CNS, with manifest possibilities for future clinical research.
Use the tab above to find multimedia from this event.
Presentations available from:
David Begley, PhD (King's College London, London, UK)
Adam Chodobski, PhD (The Warren Alpert Medical School of Brown University)
Conor P. Foley, PhD (Weill Cornell Medical College)
Damir Janigro, PhD (Cleveland Clinic)
Brian K. Kaspar, PhD (Research Institute at Nationwide Children's Hospital)
Elisa E. Konofagou, PhD (Columbia University)
Joel S. Pachter, PhD (University of Connecticut Health Center)
Image credit: The Blood-Brain Barrier Laboratory, University of Connecticut Health Center
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William Frey II
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Jo Ann Dumin, PhD
Jo Ann Dumin earned a BS in Biology from Rensselaer Polytechnic Institute. Her graduate work was performed at Albany Medical College where she obtained a MS and PhD in Biochemistry and Molecular Biology under the guidance of John Jeffrey. Dumin 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, she 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, Dumin 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, Dumin obtained a position in the Groton Neuroscience Department. During her tenure, the lab supported biomarker development for Alzheimer's disease, identified Neuroinflammation targets, and assessed technologies that may increase the ability of therapeutics to cross the blood–brain barrier. Dumin has significant expertise in inflammation as well as aging and tissue repair mechanisms in disease states. She has been involved in a wide range of projects for both small molecule therapeutics and biotherapeutics as well as indication discovery efforts. She is currently at Satori Pharmaceuticals which is developing a small molecule inhibitor for the treatment of Alzheimer's disease.
Mercedes Beyna, MS
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. Beyna 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 S. Pachter, PhD
Joel 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, 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. He was promoted to full Professor in 2003. Pachter's major research interests are the blood–brain barrier and neuroinflammation. Most recently, he has turned his attention to the emerging technique of laser capture microdissection, applying this to exploring gene regulation along the neurovascular unit in situ. Pachter is on the editorial board of Microvascular Research, and has sat (and continues to sit) on study sections at the NIH and National Multiple Sclerosis Society.
Jennifer Henry, PhD
The New York Academy of Sciences
Jennifer Henry received her PhD in plant molecular biology from the University of Melbourne, Australia, with Paul Taylor at the University of Melbourne and Phil Larkin at CSIRO Plant Industry in Canberra, specializing in the genetic engineering of transgenic crops. She became the Editor of Functional Plant Biology at CSIRO Publishing, and then moved to New York for her appointment as Publishing Manager with Nature Publishing Group, where she was responsible for the publication of a range of biomedical journals. Jennifer Henry joined the Academy in 2009 as Director of Life Sciences, and is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology, under the auspices of the Academy's Frontiers of Science program. She also generates alliances with organizations interested in developing programmatic content.
David J. Begley, PhD
David J. Begley, PhD is Senior Lecturer in Physiology at King's College London. He heads a laboratory in the Pharmaceutical Sciences Division at King's 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 60 peer-reviewed papers on blood–brain barrier (BBB) function and drug delivery to the CNS and has contributed more than 16 chapters on blood–brain barrier and CNS drug delivery to edited volumes. Begley was the Friedrich Mertz Stiftungsgast professor, Johann Wolfgang Goethe-Universität, Frankfurt for the academic year 1997–1998 and was a visiting Academic in Residence, GlaxoSmithKline 2005–2007. 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
Adam Chodobski is Associate Professor and Director of Neurotrauma and Brain Barriers Research Laboratory in the Department of Emergency Medicine. A 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. 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 Chodobski and 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.
Conor P. Foley, PhD
Conor Foley is a Post-doctoral Fellow in Radiology at Weill Cornell Medical College. There he designs, fabricates, and tests endovascular microcatheters for translational mouse models of intra-arterial drug delivery and performed both clinical and pre-clinical imaging research. Foley did his doctoral work in the Department of Chemical Engineering at Cornell University where he designed and fabricated a chronically implantable microfluidic probe and a biodegradable insertion scaffold for convection-enhanced drug delivery to neural tissue. He also developed a novel small animal model of reversible stroke and used multiphoton microscopy to characterize the real-time transport of nanoparticles in brain tissue. In addition, Foley created computational models of drug delivery in the brain. He holds a Bachelor of Engineering with honors in Chemical Engineering from University College Dublin.
William H. Frey II, PhD
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 industries. 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. 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, 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 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. Frey earned his BA in Chemistry at Washington University in 1969 and PhD in Biochemistry at Case Western Reserve University in 1975.
Damir Janigro, PhD
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 the 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. 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 U.S. and 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 K. Kaspar, PhD
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, where he specialized 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, 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. Kaspar serves as an editor for the journal Molecular Therapy.
Elisa E. Konofagou, PhD
Elisa Konofagou is currently an Associate Professor of Biomedical Engineering and Radiology, and Director of the Ultrasound and Elasticity Imaging Laboratory at Columbia University. She is also a technical committee member of the IEEE in Engineering in Medicine and Biology, IEEE in Ultrasonics, Ferroelectrics and Frequency Control, and the Acoustical Society of America. 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. She is author of over 120 published articles in the aforementioned fields. In addition, Konofagou is a technical committee member of 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. Konofagou 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 S. Pachter, PhD
Yao-Sheng Tung was born in Taipei, Taiwan. He received his BS and MS degrees from National Taiwan University, in Taipei, Taiwan. He was a research assistant in National Taiwan University Hospital in 2006. In September 2007, he enrolled in Columbia University's PhD program. Tung's research interests are in ultrasound therapy with microbubbles, and cavitation effects. Tung is conducting his PhD research in the Ultrasound and Elasticity Imaging Laboratory at Columbia University, under the guidance of principal investigator Elisa E. Konofagou.
Daniel Duzdevich specializes in research techniques that probe individual biological reactions and molecules. He is fascinated by the visual dimension of science and language's role in the scientific enterprise. Daniel earned his MPhil in biology at the University of Cambridge and is currently a PhD candidate at Columbia University in the laboratory of Prof. Eric C. Greene. He has been a member of the New York Academy of Sciences since 2005.