The blood-brain barrier (BBB) maintains essential brain homeostasis, but as a result can impede delivery of new therapies. Antibodies and new drugs hold promise for treating brain diseases and disorders; however, their utility is often limited by poor
penetration across the BBB. The second annual Blood-Brain Barrier conference will examine newly discovered mechanisms of the BBB, including the mechanisms behind a leaky BBB, and how that affects our understanding of brain penetration and how we deliver
therapies to the brain. The conference will bring together academic and industry experts to highlight updates and case studies on large molecule delivery and cell models.
Final Agenda
Wednesday, June 15
7:00 am Registration and Morning Coffee
8:25 Chairperson’s Opening Remarks
Robert D. Bell, Ph. D., Principal Scientist, Integrative Neuroscience, Pfizer
»8:35 KEYNOTE PRESENTATION: BBB BREAKDOWN IN NEURODEGENERATIVE DISEASES: CONTRIBUTIONS TO DISEASE PATHOGENESIS AND IMPLICATIONS FOR DRUG DELIVERY
Berislav Zlokovic, M.D., Ph.D., Director, Zilkha Neurogenetic Institute, Keck School
of Medicine
The blood-brain barrier (BBB) limits the entry of neurotoxic blood-derived products, pathogens and cells into the central nervous system (CNS) and in the same time restricts delivery of most therapeutic agents to the CNS. The BBB is damaged in Alzheimer’s
disease (AD) and other neurodegenerative disorders, and in models of these neurodegenerative disorders. We will discuss contributions of BBB breakdown to disease pathogenesis and implications for CNS drug delivery.
9:05 Characterization of the Non-Conventional Blood Meningeal Barrier and Its Role during Homeostasis and Neuroinflammation
Jorge Alvarez, Ph.D., Assistant Professor, Pathobiology, University of Pennsylvania
Using novel human in vitro models of the BBB and BMB, we found that their inherent barrier properties are differentially influenced by astrocyte-secreted factors. Careful examination of these CNS barrier sites will advance our understanding of the mechanisms
regulating barrier function and underlying the development of neuroinflammation.
9:35 Predictive Understanding of Blood-Brain Barrier Transport Mechanisms to Counter Chemical and Biological Weapons Threats
Brian Pate, Physical Scientist, Chemical and Biological Technologies Department, Defense Threat Reduction Agency
The essential protective nature of the blood-brain barrier challenges development of centrally acting medical countermeasures to chemical and biological weapons. Recent efforts driven by the U.S. Department of Defense have exploited multifaceted toolsets
to foster new models and understanding of selective human blood-brain barrier transport pathways and their molecular, cellular, and systemic modulation within baseline and induced dynamic biochemical environments.
10:05 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:50 Regionally Distinct Astrocyte Interferon Signaling Promotes Blood-Brain Barrier (BBB) Integrity during Neurotropic Viral Infection
Robyn S. Klein, M.D., Ph.D., Professor, Internal Medicine, Pathology & Immunology, Anatomy &
Neurobiology, Washington University School of Medicine
We demonstrate that type I interferon receptor (IFNAR) signaling in astrocytes regulates BBB permeability and protects the cerebellum from infection and immunopathology. Interferon stimulated genes (ISGs) had higher basal and interferon-induced expression
in human and mouse cerebellar astrocytes compared to cortical astrocytes. Our data identify cerebellar astrocytes as key responders to viral infection and highlight distinct innate immune responses in astrocytes from evolutionarily disparate regions
of the CNS.
11:20 Adhesion Molecules of the BBB and Neuroinflammation
Alexandre Prat, M.D., Ph.D., FRCPC, Professor, Neuroscience, Université de Montréal
This presentation will provide a short overview of the progresses that were made over the last 5 years to identify novel pathways that are involved in the selective recruitment of specific immune cells to the CNS and in the process of CNS immune quiescence.
These molecules are currently seen as the basis for the development of future therapies in neuroinflammatory disorders, including multiple sclerosis.
11:50 In vivo Microscopy-Based Assay for Brain Distribution of Biologics: From a Case-Study to the Industry Standard
Leonard Khiroug, CSO, Neurotar Ltd.
Conventional brain exposure assays either lack longitudinality (IHC and ELISA) or have low spatial resolution insufficient for separation of cellular/subcellular compartments (radiolabelled imaging and microdialysis). Neurotar’s in vivo
microscopy assay overcomes these limitations by quantitatively imaging brain exposure of fluorescently labelled biologics in living mouse’s cortex with sub-micrometer resolution.
12:05 Sponsored Presentation (Opportunity Available)
12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:50 Session Break
1:40 Chairperson’s Remarks
William Elmquist, Pharm.D., Ph.D., Professor, Pharmaceutics, University of Minnesota
1:50 Low Intensity Pulsed Focused Ultrasound and Microbubbles Results in Sterile Inflammatory Response in the Rat Brain
Zsofia Kovacs, Ph.D., Postdoctoral Fellow, Radiology and Imaging Sciences, National Institutes
of Health
Very little is known about the graded cellular and molecular responses in the brain following pFUS coupled with MB exposures through the disruption of the BBB (BBBD). Proteomic changes in the brain associated with BBBD indicate that pFUS + MB
rapidly effects to the cerebral vasculature as evident by BBBD, in addition to the shockwave from MB collapse, induces mild stress within various cellular elements in the neurovascular unit.
2:20 Imaging of BBB Opening Induced by Ultrasound
Kullervo Hynynen, Ph.D., Professor, Medical Biophysics, University of Toronto
Ultrasound combined with intra-vascular microbubbles can be used to focally and temporarily open the BBB in image guided locations. We have explored the use of MRI, ultrasound, and two-photon imaging to detect, study, and monitor the opening.
In this presentation, our experience with these methods will be reviewed and potential applications discussed.
2:50 Refreshment Break in the Exhibit Hall with Poster Viewing
3:35 Pharmacokinetics of CNS Penetration
Andreas Reichel, Ph.D., Vice President, Head, Research Pharmacokinetics, Bayer Pharma
While target site concentrations in most peripheral organs are in direct correspondence with unbound plasma concentrations, this may not be the case for targets within the CNS due to the existence of the blood-brain barrier. The talk will focus
on the PK parameters and PK processes which are key in controlling the unbound concentrations in brain as most relevant effect compartment for CNS drug efficacy.
4:05 Using in vitro Transporter Studies and Preclinical Animal Models to Predict Brain Penetration of P-gp and BCRP Substrates in Humans
Bo Feng, Ph.D., Senior Principal Scientist, Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer, Inc.
It has been a big challenge to predict brain penetration of efflux transporter substrates in humans. This presentation will discuss species differences of efflux transporters at blood-brain barrier and what the predictability of preclinical
species is, including rat and monkey. Additionally, the relationship between CSF and unbound brain concentrations of brain transporter substrates in monkey and the translation to humans will be discussed.
4:35 Translational Strategy for Predicting Brain Penetration: From in vitro Transporter Data to Human Brain Distribution
Patrick Trapa, Ph. D., Lead, PDM Neuroscience Quantitative Translation, Pfizer
Accurate prediction of brain penetration requires the incorporation of in silico, in vitro, and in vivo approaches. Physiologically based pharmacokinetic modeling reduces the complexity of the blood-brain barrier to a simplified framework
and integrates the key information. This presentation outlines the high-throughput methodology in place at Pfizer.
5:05 Three-Dimensional Dynamic Blood-Brain Barrier Model
Monica Moya, Ph.D., Research Engineer, Materials Engineering Division, Lawrence Livermore
National Laboratory
Current in vivo models of the BBB pose interspecies differences while traditional in vitro models using transwells fail to capture actual in vivo permeability rates and lack physiological relevance. We have developed a dynamic microfluidic
3D human cell culture platform to more accurately investigate compound permeability from the bloodstream to the CNS using a second on-chip platform we have also developed. This talk will describe our BBB model and focus on the drug
clearance and interaction with our second CNS on chip platform.
5:35 Welcome Reception in the Exhibit Hall with Poster Viewing
6:45 Close of Day
Thursday, June 16
7:00 am Registration.
7:30 Interactive Breakout Discussion Groups with Continental Breakfast
This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants.
Topic: Influence of Tumor-Induced Changes in the BBB on Drug Delivery/Efficacy
Moderator: William Elmquist, PharmD, PhD, Professor, Pharmaceutics, University of Minnesota
- Heterogeneous effects of tumor growth on BBB integrity
- Influence of anti-angiogenic agents on BBB permeability and subsequent drug delivery
- Imaging to determine drug delivery (PET, MRI, MALDI-MS)
Topic: Cells, Proteins, Small Molecules: What Best to Deliver to the Brain?
Moderator: Lois A. Lampson, Ph. D., Associate Professor of Neurosurgery, Brigham & Women’s Hospital, Harvard Medical School
- Therapy for the brain can exploit cells, antibodies or other large proteins, small molecules
- These differ in the ease with which they can be made to enter the brain, move within the brain, and (if necessary) enter neural cells
- They differ in the ways in which they can interact with and affect their targets
- We will consider and compare the strengths and weaknesses of each kind of material, for delivery of therapy to the brain.
Topic: Delivery of Biotherapeutics to the Brain: Controversies, Successes, and Future directions
Moderator: Robert D. Bell, Ph. D., Principal Scientist, Integrative Neuroscience, Pfizer
- Facilitate an open discussion around the number of delivery approaches and technologies that have not work out.
- Discuss current leading approaches that have been validated across independent researchers and are in clinical development.
- Gather opinions on the future of biotherapeutic drug delivery
8:35 Chairperson’s Remarks
Per-Ola Freskgard, Ph.D., Vice Director and Senior Leader, Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.
8:45 Safely Crossing the BBB: How Do Cells Manage to Do It?
Lois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s
Hospital, Harvard Medical School
Delivering therapy across the BBB faces two kinds of challenges. One challenge is the BBB itself. A different kind of challenge is that modulation of the BBB must be well-regulated. Indeed, regulatory balance is a general concern, as seen,
for example, with Immunotherapy. Intriguingly, blood-borne cells are able to meet both challenges: to enter the brain, safely. Considering how cells do this can give both technical and conceptual insight as we consider alternative
approaches to delivering therapy across the BBB.
9:15 Novel Human Stem Cell-Derived in vitro BBB Model and Its Utility in Evaluating CNS-Targeting Biologics
Mahmud Bani, Ph.D., Team Leader, Senior Research Officer, Translational Bioscience,
National Research Council Canada
We have developed and characterized a human amniotic fluid-iPSC-derived in vitro model, which reproduces salient molecular and functional features of the blood-brain barrier (BBB), including high TEER, polarization of transporters, and
modulation by ‘brain’ microenvironment. This model is useful for assessing the transport of both synthetic and biologic CNS-targeting therapeutics. In particular, we have characterized the transport of various antibodies
against receptors that undergo receptor-mediated transcytosis (Molecular Trojan Horses), and their ability to deliver various cargos.
9:45 Blood-Brain Barrier Penetrating IgG-Fusion Proteins for the Treatment of Human Lysosomal Storage Disorders
Ruben Boado, Ph.D., Vice President, R&D, Cofounder, ArmaGen
Lysosomal enzymes are large molecule drugs that do not cross the blood-brain barrier. The BBB-penetration of enzyme therapeutics is enabled by re-engineering the recombinant enzyme as bi-functional IgG fusion proteins, wherein the IgG
domain targets a specific endogenous receptor-mediated transporter system within the BBB, such as the human insulin receptor. Several bi-functional IgG-fusion proteins have been engineered using a genetically engineered monoclonal
antibody directed to the BBB HIR as the transport domain. First in-human clinical trials are in progress.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 Influence of BBB Transporters on the Delivery of Molecularly-Targeted Agents to Primary and Secondary Brain Tumors
William Elmquist, Pharm.D., Ph.D., Professor, Pharmaceutics, University of
Minnesota
This talk will focus on the issues surrounding effective drug delivery to the invasive cells in brain tumors, both primary and metastatic. Many of the newer targeted anti-cancer agents have impressive inhibitory action against signaling
pathways that drive tumor growth. However, they have been ineffective in treating brain tumors. These molecularly-targeted inhibitors are often substrates for active efflux transporters at the BBB, and this delivery-limiting mechanism
must be overcome before these inhibitors can be adequately tested in clinical trials.
11:30 Sorting of Endogenous Immunoglobulins by Endothelial Cells at the Blood-Brain Barrier
Ludovic Collin, Laboratory Head, pRED RICB, F. Hoffmann-La Roche
The low endocytosis of brain endothelial cells (BECs) is believed to prevent delivery of immunoglobulins to the brain parenchyma. By using quantitative high-resolution microscopy, we found for the first time a steady-state accumulation
of endogenous mIgG in intracellular vesicles in BECs. Our data challenge the established notion of low vesicular transport as a hallmark of the BBB.
12:00 pm Bridging Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:30 Session Break
1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing
1:45 PLENARY KEYNOTE SESSION
3:30 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 Close of Conference