Cambridge Healthtech Institute’s 5th Annual

Blood-Brain Barrier

Opportunities, New Targets, Models and Tools, and Delivering Therapy to the Brain

June 19-20, 2019

Antibodies and new drugs that are promising for treating brain diseases and disorders are often limited by poor brain exposure. Research is focused on examining new ways to deliver drugs to the brain, including gene therapy and treatment of the BBB’s microvessels. CHI’s 5th Annual Blood-Brain Barrier conference strives to bring you the hottest topics and biggest opportunities in discovery and development of highly efficacious therapeutic agents against CNS disorders and innovative strategies for delivering therapies across the blood-brain barrier (BBB). It will focus on the key areas of understanding BBB transport and dysfunction in disease through a series of case studies and cutting-edge research presentations. This conference will address questions surrounding BBB permeability, blood flow, translational research, and biomarkers of BBB breakdown. Special attention will be paid to in vivo models and tools that are available to investigate BBB transport and pathology in disease. The conference will also provide updates from the industry on antibody delivery and transport across the BBB.

Final Agenda


Wednesday, June 19

12:00 pm Registration Open

12:00 Enjoy Lunch on Your Own

12:30 Transition to Plenary


2:20 Booth Crawl and Dessert Break in the Exhibit Hall with Poster Viewing

2:25 Meet the Plenary Keynotes

Cityview 1

3:05 Chairperson’s Remarks

Nathalie Y.R. Agar, PhD, Associate Professor, Neurosurgery, Brigham and Women’s Hospital

3:10 Molecular Mechanisms Governing the Formation and Regulation of the Blood Brain Barrier

Gu_ChenguaChenghua Gu, DVM & PhD, Professor of Neurobiology, Harvard Medical School

Transcytosis is actively inhibited in the CNS endothelial cells for BBB integrity. We identify that Mfsd2a acts at the BBB to regulate a specific vesicular trafficking pathway, caveolae-mediated transcytosis, in CNS endothelial cells by suppressing caveolae pit formation and cargo uptake at the plasma membrane. The lipids transported by Mfsd2a establish a unique lipid environment that inhibits caveolae vesicle formation in CNS endothelial cells to suppress transcytosis and ensure BBB integrity.

3:30 Integrated Mapping of Pharmacokinetics and Pharmacodynamics in Brain Tumors

Agar_NathalieNathalie Y.R. Agar, PhD, Associate Professor, Neurosurgery, Brigham and Women’s Hospital

We discuss time-dependent processing artifacts, underscoring the importance of immediate analysis. ivLESA-MS represents a rapid in vitro metabolomic method, which precludes the need for quenching, cell harvesting, sample preparation, and chromatography, significantly shortening preparation and analysis time while minimizing processing artifacts.

3:50 Molecular Insight into Assessment of Unbound Drug Concentration in Brain Regions of Patients with Alzheimer’s Disease

Loryan_IrenaIrena Loryan, PhD, Researcher, Department of Pharmaceutical Biosciences, Translational PKPD, Uppsala University

For preclinical and clinical assessment of therapeutically relevant unbound brain concentrations, the pharmacokinetic parameter fraction of unbound drug in the brain is commonly used to compensate total concentration for nonspecific brain tissue binding (BTB). The talk will be focused on studies providing evidence, with potential molecular mechanisms, of regional differences in drug BTB in rats and humans, opposing currently established assumptions on similar BTB between species, regions, and Alzheimer’s disease.

 4:10 Differential Expression of Receptors and Proteins Involving Receptor-Mediated Transcytosis (RMT) Across Species

Wandong Zhang, M.D., PhD, Senior Research Officer, Human Health Therapeutics Research Centre, National Research Council Canada

RMT is a commonly used pathway for brain delivery of biologics. However, the expression of receptors potentially involving RMT is uncharacterized in brain/vessels and peripheral tissues/vessels of different species.  Using next-generation sequencing, we generated an expression ‘map’ of RMT receptors in brain cells/vessels and peripheral tissue/vessels of mouse, rat and human. Understanding the expression and distribution of these receptors in different species is critical for translational studies in brain drug delivery. 

4:40 SELECTED POSTER PRESENTATION: Improving the Ability of Hematopoietic Stem Cells in Generating Microglia-Like Progeny Upon Transplantation 


Annita Montepeloso, Graduate Student, Biffi Lab, Gene Therapy Program, Dana Farber/Boston Children's Cancer and Blood Disorders

Hematopoietic stem and progenitor cells (HSPCs) contribute to brain myeloid cell turnover, upon administration of proper conditioning. Engrafted cells can act as vehicles for therapeutics and modulators of inflammation. However, the impact of this approach is affected by the slow pace of microglia reconstitution. To fasten this process, we identified a key factor to be targeted that may enhance the ability of hematopoietic cells to generate microglia-like progeny upon transplantation.

5:10 4th of July Celebration in the Exhibit Hall with Poster Viewing

5:30-5:45 Speed Networking: Oncology

6:05 Close of Day

5:45 Dinner Short Course Registration

6:15 Dinner Short Course*

*Separate registration required .


Thursday, June 20

7:15 am Registration Open

7:15 Breakout Discussion Groups with Continental Breakfast 

Cityview 1

8:10 Chairperson’s Remarks

Danica Stanimirovic, MD, PhD, Director, Translational Bioscience Department, Human Health Therapeutics Portfolio, National Research Council of Canada

8:15 Utilizing Block Copolymers as Therapeutic Agents to Mitigate BBB Disruption

Azarin_SamiraSamira M. Azarin, PhD, Assistant Professor, Department of Chemical Engineering and Materials Science, University of Minnesota

Poloxamer 188, a triblock copolymer of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), has been widely studied as a membrane stabilizer in various tissues and has shown neuroprotective effects in brain injury models. This talk will focus on the exploration of novel PEO-PPO diblock copolymers as more effective alternatives to Poloxamer 188 for mitigating BBB disruption using stem cell-derived models of the human BBB.

8:45 Platform Technology for Treatment of Brain Disorders with Blood-Brain Barrier Penetrating Igg-Fusion Proteins: Preclinical and Clinical Update

boado_rubenRuben Boado, PhD, Vice President, Research & Development/Co-Founder, ArmaGen, Inc.

Protein therapeutics can be re-engineered as brain-penetrating IgG-bifunctional fusion proteins for the treatment of CNS disorders. The IgG domain targets a specific endogenous receptor-mediated transporter system within the BBB, i.e. human insulin receptor (HIR). The therapeutic domain of the fusion protein exerts the pharmacological effect in the brain once across the BBB. Pre-clinical and first in human proof of concept phase II clinical trial in Hurler disease will be discussed.

9:15 KEYNOTE PRESENTATION: Blood-Brain Barrier-Crossing Single-Domain Antibodies Targeting IGF1R: Mechanism of Action and Preclinical Assessment

Stanimirovic_DanicaDanica Stanimirovic, MD, PhD, Director, Translational Bioscience Department, Human Health Therapeutics Portfolio, National Research Council of Canada

Insulin growth factor 1 (IGF1) is transported across the blood-brain barrier (BBB) via a receptor-mediated transcytosis. To exploit IGF1 transcytosis route for therapeutic delivery across the BBB, single-domain antibodies (sdAb) selective for IGF1 receptor (IGF1R) were raised and optimized for binding affinity, biophysical properties, receptor binding epitopes, and species cross-reactivity. Enhanced cargo delivery across the BBB (including peptides, antibodies, enzymes and nanocarriers) was demonstrated in vitro and in animal models.

View Speaker Interview

9:45 In Vivo Analysis of BBB, Cells and Organelles Using a Unique Microscopy Platform

Khiroug_LeonardLeonard Khiroug, PhD, CSO, Neurotar Ltd

Longitudinal microscopic analysis of blood vessels, neurons or glial cells is especially valuable when performed in their natural environment, i.e. in a live animal’s brain. We shall discuss a range of preclinical contract-research studies that used our in vivo multiphoton imaging platform in either anesthetized or awake, behaving mice.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Poster Winner Announced

11:00 Protein Engineering For Enhanced And Sustained CNS Exposure Of Neuro-Therapeutic Antibodies

Smith_BenjaminBenjamin Smith, PhD, Scientist, Biologics Drug Discovery Biogen

The single domain antibody FC5 engages receptor-mediated transcytosis and is a promising BBB carrier. Here the humanization and stability engineering of FC5 and design of FC5 bispecifics with antibodies against neurodegenerative disease targets will be described. Enhanced BBB penetration of the bispecifics in an in vitro BBB model as well as CNS pharmacokinetics in rats and monkeys dosed at therapeutically relevant doses by systemic injections will be shown.


11:30 Image-Guided Opening of the Blood-Brain Barrier and Intra-Arterial Drug Delivery

Piotr_WalczakPiotr Walczak, MD, PhD, Associate Professor, Radiology, Johns Hopkins University

Endovascular neurointervention revolutionized the treatment of stroke and its applications are expanding. Intra-arterial drug delivery is a potentially excellent route for selective high concentration targeting of specific brain structures, however, the blood-brain barrier (BBB) and variable biodistribution have been significant impediments to this approach. We have developed techniques for the image-guided opening of the BBB and intraarterial drug delivery making the procedure precise, predictable and reproducible.

12:00 pm Differentiation of Human Pluripotent Stem Cells into High Resistance Barrier-Endothelial Cells Using Genome Editing, Genomics and Chemogenomic Library Screening Approaches

Roudnicky_FilipFilip Roudnicky, PhD, Senior Scientist, Disease Relevant Cellular Assays, F. Hoffmann-La Roche Ltd.

We will present a method to generate high-resistance barrier endothelial cells from human pluripotent stem cells (hPSCs). We have generated using genome editing a claudin 5 (CLDN5) transcriptional reporter in hPSCs to serve as a surrogate marker for high-resistance endothelial barrier. Finally, using evidence-based chemical-probe library, designed to span many molecular targets, we have screened for chemical-probes that induce CLDN5 expression in differentiated endothelial cells.

12:30 SELECTED POSTER PRESENTATION: Modeling The Neurovascular Niche In An Autologous Stem Cell Derived 4-Organ-Chip

Leopold Koenig, MSc, Scientist, Contract Development, TissUse GmbH


Understanding the ability to pass the blood-brain barrier is crucial for assessing safety and efficacy in the development of neurological-active compounds. Therefore, we have developed an induced pluripotent stem cell-derived neuronal / blood-brain barrier model, which is now going to be integrated into the TissUse 4-Organ-Chip. Here we show the first data of the co-culture of the neuronal / blood-brain barrier model with hepatocyte-spheroids from the same donor.

12:50  SELECTED POSTER PRESENTATION: Investigating Receptor Mediated Transcytosis with Advanced Blood-Brain Barrier Models

Roberto Villasenor Solorio, PhD, Senior Scientist, Investigative Safety, Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel

Advanced microscopy recently enabled the identification of new pathways for receptor mediated transcytosis across the blood-brain barrier. The precise mechanisms that regulate such pathways are still unknown. Here, we will present our current efforts to dissect the molecular regulation of receptor mediated transcytosis across the Blood-Brain Barrier using human advanced cellular models. Our goal is to accelerate the development of next-generation brain delivery platforms for biologics. 

1:05 Enjoy Lunch on Your Own

1:35 Dessert and Coffee Break in the Exhibit Hall with Poster Viewing

1:45-2:00 Speed Networking: Last Chance to Meet Potential Partners and Collaborators!


2:20 Chairperson’s Remarks

Piotr Walczak, MD, PhD, Associate Professor, Radiology, Johns Hopkins University

2:25 A Perfused Human Blood–Brain Barrier On-A-Chip for High-Throughput Assessment of Barrier Function and Antibody Transport

Wevers_NienkeNienke R. Wevers, MSc, Scientist, Model Development, Mimetas BV

We present a novel model of the human blood-brain barrier (BBB) in a high-throughput microfluidic system that allows parallel culture of 40 models at once. The model comprises brain endothelial cells, astrocytes, and pericytes and shows the formation of a functional barrier. Passage of an antibody targeting the human transferrin receptor was markedly higher than penetration of a control antibody, indicating that this model could support further discovery and engineering of antibody BBB-shuttle technologies.

2:55 In Vitro and in vivo Models to Evaluate P- gp and BCRP Activity in Regulating BBB Penetration

Xiao_GuangqingGuangqing Xiao, PhD, Director, Drug Metabolism & Pharmacokinetics, Discovery Sciences, Sunovion Pharmaceuticals, Inc.

The presentation will give an overview of expression of Pgp and BCRP in BBB and BCSFB, species difference in expression, how Pgp and BCRP regulate BBB penetration, in vitro models to identify Pgp and BCRP substrates, and preclinical in vivo models to assess brain penetration, and how to use in vitro and in vivo models to identify compounds with good brain penetration.

3:25 Exploring the Utility of iPSC-Derived 3D Cortical Spheroids in the Detection of CNS Toxicity


Qin Wang, PhD, Scientist, Drug Safety Research and Evaluation, Takeda

Drug-induced Central Nervous System (CNS) toxicity is a common safety attrition for project failure during discovery and development phases due low concordance rates between animal models and human, absence of clear biomarkers, and a lack of predictive assays. To address the challenge, we validated a high throughput human iPSC-derived 3D microBrain model with a diverse set of pharmaceuticals. We measured drug-induced changes in neuronal viability and Ca channel function. MicroBrain exposure and analyses were rooted in therapeutic exposure to predict clinical drug-induced seizures and/or neurodegeneration. We found that this high throughput model has very low false positive rate in the prediction of drug-induced neurotoxicity.

3:55 Linking Liver-on-a-Chip and Blood-Brain-Barrier-on-a-Chip for Toxicity Assessment

lelievre_SophieSophie Lelievre, DVM, PhD, LLM, Professor, Cancer Pharmacology, Purdue University College of Veterinary Medicine

One of the challenges to reproduce the function of tissues in vitro is the maintenance of differentiation. Essential aspects necessary for such endeavor involve good mechanical and chemical mimicry of the microenvironment. I will present examples of the management of the cellular microenvironment for liver and blood-brain-barrier tissue chips and discuss how on-a-chip devices may be linked for the integrated study of the toxicity of drugs and other molecules.

4:25 Close of Conference

Arrive early to attend Tuesday, June 18 - Wednesday, June 19

CNS Targets and Translational Strategies