Blood-Brain Barrier Track Header

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.


Recommended All Access Package:

June 14 SC10: Molecular Imaging of the Blood-Brain Barrier*

June 15-16: Blood-Brain Barrier

June 16-17: Property-Based Drug Design in Medicinal Chemistry

* Separate registration required.


Final Agenda

Day 1 | Day 2 | Speaker Biographies | Download Brochure


Wednesday, June 15

7:00 am Registration and Morning Coffee


UNDERSTANDING AND UTILIZING MECHANISMS OF THE BBB

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_ZlokovicBerislav 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_AlvarezJorge 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_PateBrian 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_KleinRobyn 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_PratAlexandre 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 KhirougLeonard 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


UNDERSTANDING AND PREDICTING BRAIN PENETRATION

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_KovacsZsofia 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_HynyenKullervo 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_ReichelAndreas 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_FengBo 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_MoyaMonica 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

Day 1 | Day 2 | Speaker Biographies | Download Brochure


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

 

DELIVERING THERAPIES ACROSS THE BBB

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_LampsonLois 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_BaniMahmud 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_BoadoRuben 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_ElmquistWilliam 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_CollinLudovic 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



Day 1 | Day 2 | Speaker Biographies | Download Brochure

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