Cambridge Healthtech Institute’s 2nd Annual

Advancing CNS Biotherapeutics and Crossing the Blood-Brain Barrier

Opportunities, New Targets, Models and Tools, and Delivery

January 14-15, 2019

Cambridge Healthtech Institute’s 2nd Annual Advancing CNS Biotherapeutics and Crossing the 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). This conference will provide platform to brainstorm ideas and share new research on topics such as the biologics for CNS targets and biomarkers, brain cancer, neurodegeneration, neuroinflamation, neuroimmunology, alteration of CNS/BBB barriers due to injury or disease, preclinical models, neuroimaging, tools for prediction of brain penetration, and updates from the industry on topics such as antibody delivery and vector-mediated transport across BBB. This conference will feature stimulating discussions and a friendly place to network with peers. We invite you to present a poster, or to attend to learn from and network with the leading experts from around the globe.

Final Agenda

SUNDAY, JANUARY 13

4:00 - 6:00 pm Pre-Conference Registration (Sapphire West Foyer)

MONDAY, JANUARY 14

7:00 am Registration and Morning Coffee (Sapphire West Fire)

NEW TARGETS, OPPORTUNITIES AND DRUG DELIVERY FOR BIOLOGICS
Sapphire 410

9:00 Welcome by Conference Organizer

Nandini Kashyap, Conference Director, Cambridge Healthtech Institute

9:05 Chairperson’s Opening Remarks

Miroslaw Janowski, MD, PhD, Associate Professor, Radiology, Johns Hopkins University

KEYNOTE PRESENTATION

9:10 Nanoparticles, Cells and Exosomes for CNS Therapeutics

Alexander (Sasha) Kabanov, PhD, DrSci, Distinguished Professor, Eshelman School of Pharmacy, University of North Carolina and Chapel Hill

Polyion complexes, cell drug carriers and exosomes are engineered for treatments of neurodevelopmental and neurodegenerative diseases. Polyion complexes entrap antioxidant enzymes, stoichiometric and catalytic scavengers of organophosphorus toxins (OP) and neurotrophins to treat obesity, stroke, Parkinson’s disease (PD), OP poisoning, and lysosomal storage diseases (LSD). Genetically modified macrophages and exosomes are natural delivery vectors for proteins and nucleic acids as exemplified in experimental models of PD and LSD.

9:50 Differentiation of Human Pluripotent Stem Cells into High Resistance Barrier-Endothelial Cells Using Genome Editing, Genomics and Chemogenomic Library Screening Approaches

Filip 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 a large number of molecular targets, we have screened for chemical-probes that induce CLDN5 expression in differentiated endothelial cells.

10:20 Networking Coffee Break (Sapphire & Aqua West Foyer)

10:45 Intra-Arterial Delivery of Antibodies to the Central Nervous System

Miroslaw Janowski, MD, PhD, Associate Professor, Radiology, Johns Hopkins University

Antibodies are increasingly used as therapeutic agents, though blood-brain barrier (BBB) hampers their penetration to the central nervous system (CNS). We are witnessing tremendous advances in development of endovascular tools with an excellent safety profile. Intra-arterial route increases delivery of antibody to the CNS and preceding it with hyperosmolar BBB opening further increases efficiency of this process. However, hyperosmolar BBB opening does not improve BBB penetration of intravenously administered antibody.

11:15 Boosting Brain Uptake of a Therapeutic Antibody through Conjugation to an Aptamer against Transferrin Receptor

Dongping He, MS, Senior Scientific Researcher, Biochemical & Cellular Pharmacology, Genentech/Roche

A nuclease stabilized RNA aptamer against human Transferrin receptor (huTfR) was conjugated to a bivalent therapeutic antibody. The antibody-aptamer conjugate increased brain uptake in huTfR 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 study opens up possibilities of increasing brain uptake capacities using novel multi-specific therapeutic modalities.

CNS AND BBB AT SITES OF PATHOLOGY DURING DISEASE AND INJURY
Sapphire 410

11:45 An Emerging Role for Glial Cells and Guidance Molecules in Neurodegeneration

Elizabeth Evans, PhD, Vice President, Preclinical Research, Vaccinex, Inc.

Glial cell structural and inflammatory changes may have a significant impact on neurodegeneration. Reactive gliosis, BBB integrity, and survival of glial precursor cells that repair brain lesions can be regulated by semaphorin guidance molecules. Translational mechanistic studies and preliminary brain imaging data from an ongoing Phase I/II trial with pepinemab (VX15/2503) support the hypothesis that SEMA4D antibody blockade preserves brain volume and restores metabolic activity in early Huntington’s disease.

12:15 Session Break

12:55 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

PRECLINICAL TOOLS, BIOMARKERS, ANIMAL AND CELL BASED MODELS
Sapphire 410 

2:00 Chairperson’s Remarks

Alexander (Sasha) Kabanov, PhD, DrSci, Distinguished Professor, Eshelman School of Pharmacy, University of North Carolina and Chapel Hill

2:05 3D Models to Understand Complex Neural Networks and Neurotoxicity

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

With growing interest in developing selective and potent inhibitors for the treatment of CNS diseases, there is a need to understand the challenging aspect of crossing the BBB and relevant physiological models of the BBB are germane to the success of those studies. We have developed a versatile 3D human BBB platform to more accurately investigate compound permeability from the bloodstream to the CNS (a second on-chip platform) at increasing degrees of complexity.

2:35 Modeling Vascular Dysfunction in Neurological Disease

Georgette Suidan, PhD, Scientist II, Alzheimer’s Disease and Dementia Research Unit, Biogen

Apart from the classical pathological characteristics of AD, studies have shown that the majority of AD patients present with vascular abnormalities including cerebral amyloid angiopathy, reduced cerebral blood flow (hypoperfusion) and blood brain barrier breakdown. I will give an overview of the reported literature and discuss approaches to identify and validate targets for improving vascular dysfunction in neurological disease.

3:05 Find Your Table and Meet Your BuzZ Session Moderator

3:15 BuzZ Sessions with Refreshments (Sapphire & Aqua Foyer)

Join your peers and colleagues for interactive roundtable discussions.

Click here for more details

4:30 NEW: SELECTED POSTER PRESENTATION: Engineering of Transferrin Receptor-Mediated Strategies to Increase Blood-Brain Transfer of Affibody Molecules

Linnea Hjelm, M.Sc. M.Eng., PhD Student, Protein Science, KTH Royal Institute of Technology

Affibodies are currently being investigated in many application areas. Their very small size, stability and facilitated production make affibodies attractive as fusion domains for passing the blood-brain barrier (BBB) by receptor-mediated transcytosis. In our approach, we have used directed evolution by phage display to generate affibody molecules binding to both human and murine transferrin receptor (TfR) to be used as future tools for efficient BBB transfer of various biologics.

5:00 BBB Organoids as Next-Generation in vitro Model

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

In vitro BBB models are indispensable in facilitating drug analysis and discovery. Here, we describe 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. This high-throughput model can lead to better design of brain therapeutics and improve prediction of drug delivery in a living model, paving the way for breakthrough discoveries in neuroscience.

5:30 Cell Based Models of the Human Blood-Brain Barrier

Graham Marsh, PhD, Scientist I, Translational Cellular Sciences, Biogen

Recent developments in microfluidics engineering have resulted in promising in vitro BBB models, with improved throughput and physiological relevance. Leveraging Mimetas and Nortis technology, we established two novel models of the human BBB, employing co-culture of multiple cell types in a 3D vessel microenvironment. Together with traditional Transwell systems, our BBB toolkit enables high-throughput screening and characterization of BBB penetration, supporting drug discovery and fundamental research of neurological disorders.

6:00 - 7:15 Welcome Reception in the Exhibit Hall with Poster Viewing (Sapphire Ballroom)

7:15 Close of Day

TUESDAY, JANUARY 15

8:00 am Registration and Morning Coffee (Sapphire West Foyer)

Preclinical and Clinical Updates
Sapphire 410

8:45 Chairperson’s Remarks

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

8:50 Platform Technology for Treatment of the Brain in Lysosomal Storage Disorders with Igg-Fusion Proteins: Preclinical and Clinical Update

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

Lysosomal enzymes, such as iduronase (IDUA) and sulfatases, are large molecule drugs that do not cross the blood-brain barrier (BBB). 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 (HIR). The enzyme therapeutic domain of the fusion protein exerts the pharmacological effect in brain once across the BBB. Several brain penetrating IgG-LSD fusion proteins have been engineered and validated. First in human proof-of-concept Phase II clinical trial in LSD will be discussed.

9:20 Engineering, Biomanufacturing and Preclinical Development of a Blood-Brain Barrier-Crossing, Amyloid-ß Targeting Fusion Protein

Balu Chakravarthy, PhD, Senior Research Officer, Human Health Therapeutics, National Research Council

We are developing a polypeptide (ABP) that targets aggregated amyloid-ß implicated in Alzheimer’s disease pathogenesis. To enable brain-delivery of ABP, we have engineered and produced a bi-functional fusion protein, KAL-ABP-BBB, consisting of a novel blood-brain barrier-crossing domain antibody. PK/PD studies demonstrated brain-delivery and target engagement in mouse, rat and dog models. Humanized KAL-ABP-BBB has been biomanufactured in CHOBRI and characterized in support of clinical studies led by KalGene Pharmaceuticals.

9:50 Coffee Break in the Exhibit Hall with Poster Viewing (Sapphire Ballroom)

11:00 Translational Potential of “Stapled” α-helical Neuropeptides in Eating and Neuropsychiatric Disorders

Subhi Marwari, PhD, Postdoctoral Department of Pharmacology & Department of Pharmacy, Yong Loo Lin School of Medicine, National University of Singapore

The blood-brain barrier (BBB) restricts the use of numerous therapeutic agents to target the central nervous system (CNS), posing a significant challenge to drug development efforts to treat neuropsychiatric disorders. Introducing an innovative “hydrocarbon-stapling” approach and combining with intranasal delivery technology in neuropeptide relaxin-3, we have demonstrated the potential of the neuropeptide-receptor system in pursuit of the most effective translational pharmacological strategy to reversing depression, anxiety, and related eating disorders.

11:30 Extended Q&A with Session Speakers

12:00 pm Sponsored Presentation (Opportunity Available)

12:30 Session Break

12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:10 Close of Advancing CNS Biotherapeutics and Crossing the Blood-Brain Barrier Conference