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. Cambridge Healthtech Institute’s Fourth Annual Blood-Brain Barrier conference 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

Tuesday, June 19

7:30 am Registration Open (America Foyer) and Morning Coffee (Foyer)

UNDERSTANDING BRAIN PENETRATION AND DRUG DELIVERY
Essex North West

8:15 Chairperson’s Opening Remarks

Peter Searson, PhD, Professor, Institute for Nanobiotechnology, Johns Hopkins University

8:20 Drug Delivery to the Brain: Overlooked and Underexplored Strategies to Cross the Blood-Brain Barrier

William A. Banks, MD, Associate Chief of Staff – R&D, Geriatric Research Education & Clinical Center, Veterans Affairs Medical Center & University of Washington

A brief overview will provide a working definition of the BBB and set up for these overlooked strategies. Three examples will be given: The Undiscovered Transporter with application to antisense transport into brain; Regulation of Endogenous Transporters with Small Molecules will show how to treat brain with the patient’s own hormones; Exosomes will explore the surprising finding that they cross the BBB quite readily.

8:50 Drug Delivery through the Ultrasound-Mediated Blood-Brain Barrier

Shih-Ying Wu, PhD, Translational Fellow / Postdoctoral Research Scientist, Department of Biomedical Engineering, Columbia University

Current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly non-invasive, transient, and regionally selective brain drug delivery method because of the blood-brain barrier (BBB). Focused Ultrasound (FUS) has been shown to offer the unique capability of noninvasively, locally and transiently opening the BBB. The FUS premise in brain drug delivery including clinical applications will be presented.

9:20 ApoE-Based Peptide Mediator to Deliver Proteins across the Blood-Brain Barrier: Long-Term Efficacy, Toxicity, and Mechanism

Peter Lobel, PhD, Professor, Center for Advanced Biotechnology and Medicine, Rutgers University

Sarkar and colleagues pioneered use of a peptide mediator, K16ApoE, to promote transport of intravenously-administered proteins and small molecules across the blood-brain barrier. We have explored use of K16ApoE and derivatives for acute and chronic delivery of the lysosomal enzyme TPP1 to the mouse brain. The peptide mediators are extremely useful for evaluating brain therapeutics in animal models but appear to possess intrinsic toxicity that precludes clinical applications.

9:50 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

10:35 Safety and Clinical Efficacy of a Brain-Penetrating Human IgG-Iduronidase Fusion Protein in a Phase II Study in Pediatric Patients with Severe Mucopolysaccharidosis Type I

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

A brain penetrating IgG-enzyme fusion protein comprised of iduronidase (IDUA) and a monoclonal antibody against the human insulin receptor was engineered to cross the blood-brain barrier (BBB) and to address both the neurocognitive and peripheral burden in Mucopolysaccharidosis Type I (MPS I). Neurocognitive function, somatic effects and safety of a Phase II proof-of-concept clinical trial in Hurler MPSI pediatric patients will be discussed. This represents the first-in-human clinical trial of a fusion protein engineered to cross the BBB.

11:05 Boosting Brain Uptake of a Therapeutic Antibody Through Conjugation to an Aptamer Against Transferrin Receptor

Yanmei Lu, Ph.D., Scientist, Biochemical and Cellular Pharmacology, Genentech, Inc.

The Transferrin receptor (TfR) has been shown to transport monoclonal antibodies across the blood-brain barrier in a bispecific antibody format with one arm binding to a therapeutic target and another arm binding TfR. The bispecific antibody format has its limitation in losing bivalency and apparent binding affinity, which results in weaker target engagement. Another issue is that the wt Fc domain can induce toxicity, which may limit use to only effectorless antibodies as a therapeutic. To overcome these challenges, a nuclease stabilized RNA aptamer against human TfR was conjugated to a bivalent therapeutic antibody. The antibody-aptamer conjugate increased brain uptake in human TfR transgenic mice compared to the control, and without the toxicity observed for the TfR bispecific antibody. Taking advantage of the small size of aptamers, this proof of concept study opens up possibilities of increasing brain uptake capacities using novel multi-specific therapeutic modalities.

11:35 Size-Selective Loosening of Blood-Brain Barrier by Genetic and Pharmacological Targeting of Endothelial S1P1

Keisuke Yanagida, PhD, Research Fellow, Vascular Biology Program, Boston Children’s Hospital/Harvard Medical School

The intact blood-brain barrier (BBB) restricts efficient penetration of central nervous system (CNS)-targeted drugs. Here we report the BBB-regulatory role of endothelial sphingosine 1-phosphate receptor-1 (S1P1). Endothelial-specific S1P1 knockout mice showed BBB breach for small molecular weight fluorescence tracers. Consistently, pharmacological inhibition of S1P1 led to transient BBB breach. The inhibition of brain endothelial S1P1 may be a promising strategy for efficient delivery of small molecules into the CNS.

12:05 Enjoy Lunch on Your Own

UNDERSTANDING THE BLOOD-BRAIN BARRIER IN STATES OF DISEASE
Essex North West

1:15 Chairperson’s Remarks

William A. Banks, MD, Associate Chief of Staff – R&D, Geriatric Research Education & Clinical Center, Veterans Affairs Medical Center & University of Washington

1:20 Targeting Vascular Dysfunction in Alzheimer’s Disease

Georgette L. Suidan, PhD, Principal Scientist, Lab Head, Internal Medicine Research Unit, Pfizer, Inc.

*Currently at Biogen, Inc

Apart from the classical pathological characteristics of AD, studies have shown that the majority of AD patients present with cerebrovascular abnormalities. These abnormalities include reduced cerebral blood flow (CBF) leading to impaired tissue perfusion and BBB damage resulting in increased permeability to neurotoxins. I will give an overview of the reported vascular dysfunction in AD and discuss a current project targeting a plasma protein to improve CBF and BBB integrity.

1:50 Cerebrovascular Remodeling in Neurological Disorders

Baptiste Lacoste, PhD, Assistant Professor, Cellular and Molecular Medicine/Neuroscience Program, The University of Ottawa/Ottawa Hospital Research Institute

Neurological disorders can originate from, or be perpetuated by, the brain vasculature. Acute and/or chronic abnormalities of cerebrovascular networks have been linked to the onset/progression of stroke, migraine, as well as mental illness. Treatment for many of these conditions is lacking, hence the need to identify new therapeutic targets is pressing. To illustrate these concepts, Dr. Lacoste will provide examples of cerebrovascular alterations that occur in pathological conditions.

NOVEL APPROACHES FOR BBB MODELS
Essex North West

2:20 BBB Organoids: A Next-Generation in vitro Screening Platform

Choi-Fong Cho, PhD, Instructor, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School

The presentation will focus on the utility of 3D multicellular BBB organoids made of human brain endothelial cells (ECs), brain pericytes and astrocytes as a next-generation screening model for brain-penetrating molecules. The outer surface of the organoid, composed primarily of ECs and pericytes, forms the barrier that is characterized by tight junctions and efflux-pump activity. This high-throughput model can facilitate drug development and help predict drug delivery into the brain, paving the way for breakthrough discoveries in neuroscience.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing (America Ballroom)

3:30 CNS and BBB Experimental Models with Enhanced Cellular Complexity and Architecture

Monica Moya, PhD, Research Engineer, Materials Engineering Division, Lawrence Livermore National Laboratory

In this work, we have developed a dynamic 3D human BBB culture platform to more accurately investigate compound permeability from the bloodstream to the CNS. Our BBB model is a 3D system based around a synthetic scaffold with physiologically relevant shear stress across a co-culture of astrocytes and neurons. Current work is focused on reproducing this BBB model without a synthetic fiber using a direct ink write system to 3D bioprint the BBB. To date, we have successfully cultured 3D bio-printed brain vasculature under flow conditions for three weeks.

4:00 Tissue Engineering Models of the Blood-Brain Barrier

Peter Searson, PhD, Professor, Institute for Nanobiotechnology, Johns Hopkins University

In vitro tissue-engineered models of the neurovasculature enable dynamic studies of barrier function in health and disease under controlled conditions. The incorporation of patient-derived cells has enabled the development of disease models and the study of specific mutations. Here we describe recent advances in tissue-engineered models and provide examples illustrating how they can be used to study drug delivery and disease.

4:30 Stem Cell Derived Blood-Brain Barrier Models: Applicability to Study Antibody-Triggered Receptor-Mediated Transcytosis

Anna Jezierski, PhD, Research Associate, Human Health Therapeutics, National Research Council of Canada

We have developed a human induced pluripotent stem cell-derived BBB model, composed of brain endothelial cells (iBECs), employing a novel direct monolayer differentiation protocol. This model discriminates species-selective antibody- mediated transcytosis mechanisms, is predictive of in vivo CNS exposure of rodent cross-reactive antibodies and is actively implemented into pre-clinical CNS drug discovery and development processes

5:00 Find Your Table and Meet Your Moderator

5:05 Interactive Breakout Discussion Groups

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.

Identifying Cerebrovascular Links to Neurodevelopmental Disorders

Baptiste Lacoste, PhD, Assistant Professor, Cellular and Molecular Medicine/Neuroscience Program, The University of Ottawa/Ottawa Hospital Research Institute

• What are the biggest challenges in identifying cerebrovascular links to neurodevelopmental disorders?
• What are the most promising directions for this research?
• How can this information be used to further development of drugs that pass the BBB?

Reduce, Reuse, Recycle Pharma Proprietary Therapeutic Agents for New Life in CNS Diseases

Susan Rosenbaum, J.D., Founder, Chairman & CEO, Lauren Sciences LLC

• BBB delivery
• Targeting within CNS
• Administration options

5:45 Reception in the Exhibit Hall with Poster Viewing (America Ballroom)

7:00 Close of Day

Wednesday, June 20

7:45 am Registration Open (America Foyer) and Morning Coffee (Foyer)

NANOPARTICLE DELIVERY ACROSS THE BBB
Essex North West

8:25 Chairperson’s Remarks

Jiangbing Zhou, Assistant Professor of Neurosurgery and of Biomedical Engineering, Department of Neurosurgery, Yale University

8:30 FEATURED PRESENTATION: Nanoparticle-Loaded Cells and Exosomes for Treatment of Brain Diseases

Alexander (Sasha) Kabanov, PhD, DrSci, MAE, Director, Center for Nanotechnology in Drug Delivery, Co-Director, Carolina Institute for Nanomedicine, Mescal S. Ferguso, Distinguished Professor, Eshelman School of Pharmacy, University of North Carolina and Chapel Hill

Macrophages traverse the BBB and deliver therapeutic “nanozymes” and genes (such as GDNF) to inflammatory sites in the brains of Parkinson’s disease (PD) mouse models. This produces anti-inflammatory and neuroprotective effects and improves behavior in PD models. The enzymes and neurotrophins are also packaged into exosomes secreted by macrophages to improve delivery of these proteins to the brain. The uptake of exosomes is increased in the presence of inflammation.

9:00 Nanotechnology Approaches for Drug Delivery to the Brain

Jiangbing Zhou, Assistant Professor of Neurosurgery and of Biomedical Engineering, Department of Neurosurgery, Yale University

Due to the existence of the BBB, drug delivery to the brain has been a major challenge. In this talk, I will first introduce a serial of techniques established in our laboratory for locoregional drug delivery to the brain, systemic drug delivery to the brain, and more recently, oral drug delivery to the brain. Next, I will give a few examples to show how these techniques can be utilized for treatment of neurological disorders.

9:30 V-Smart® Nanomedicines: Non-Invasive Targeted Therapeutics for Brain Diseases

Susan Rosenbaum, J.D., Founder, Chairman & CEO, Lauren Sciences LLC

V-Smart® breakthrough innovation solves greatest medical challenge in brain disease treatment -- non-invasive targeted delivery of therapeutics to brain. V-Smart® novel nanotechnology platform enables non-brain penetrant therapeutic agents to both cross BBB into brain by non-invasive administration, and target to, and selectively release at, CNS disease-specific brain sites. V-Smart® Nanomedicines pipeline of transformative therapeutics to meet medical needs of patients with brain diseases, such as Parkinson’s, ALS, GBM and Alzheimer’s.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

10:45 MR Image-Guided Nanoparticle Delivery across the Blood-Brain Barrier with Focused Ultrasound

Richard J. Price, PhD, Professor, Biomedical Engineering, University of Virginia

MR image-guided focused ultrasound can safely open the blood-brain barrier, facilitating highly localized delivery of systemically-administered brain-penetrating nanoparticles to the CNS. Our group is developing this approach as a means to treat (i) Parkinson’s disease via neurotrophic gene therapy and (ii) brain tumors via controlled-release chemotherapy, tumor suppressive miRNAs, and immunotherapies.

11:15 Delivery of Transferrin Receptor-Targeted Nanoparticles and Biologics to the Brain Via Transport Through the Blood-Brain Barrier

Torben Moos, PhD, Professor, Section for Neurobiology, Aalborg University

Directed delivery to the brain using targeted therapeutics represents a feasible method for drug delivery to the CNS. Our research group is developing targeting constructs to enable delivery of nanoparticles and biologics to the CNS in conditions without perturbation of the blood-brain barrier. In my presentation I will give an update on our attempts to transport transferrin receptor targeted nanoparticles and biologics through this blood-brain barrier.

11:45 Enjoy Lunch on Your Own

12:20 pm Dessert and Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)

1:00 PLENARY KEYNOTE SESSION
Essex South

Partnering for Sustainable Funding

The panel is designed to discuss partnering between various stake holders such as drug discovery startups, VC firms, large pharmaceutical companies and academic labs in order to advance new target discovery and preclinical research. VC companies, and pharma search & evaluation departments will be represented on the panel.

Jens Eckstein, PhD, President, SR One

Barbara K. Sosnowski, PhD, Vice President and Global Head, External R&D Innovation, Pharmatherapeutics and WRD External Partnerships, Pfizer, Inc.

Kevin Bitterman, PhD, Partner, Atlas Venture

Vivian Berlin, PhD, Director of Business Development, Life Sciences, Office of Technology Development, Harvard University

Ben Thorner, Senior Vice President and Head, MRL Business Development & Licensing, Merck

Plenary Technology Panel

Advancing Innovation in Drug Discovery and Translational Research

This year’s Plenary Technology Panel features a group of technical experts from life science technology and service companies, who share their perspectives on various trends and tools that will likely change the way in which we traditionally approach preclinical drug discovery and development. Attendees will have an opportunity to ask questions and understand the impact of recent technical advances.

Moderator: Leigh Zawel, PhD, Managing Director, MPM Capital

Ashley Rae Kark, MBS, Director, Corporate Relations, Scientist.com

Stefan Braam, PhD, Technical Director, Ncardia

Mark Paris, PhD, Director, Translational Applications, Mitra Biotech

Edgard Wood, PhD, Senior Research Director, Discovery, Charles River

2:30 Refreshment Break in the Exhibit Hall with Poster Viewing (America Ballroom)

3:10 Close of Conference