High attrition rates of novel CNS drugs indicate that current preclinical testing fails to meet the unmet needs of patients. There is growing interest in the development and application of animal models and stem cells of CNS disorders to explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic parameters of new chemical entities (NCEs).

Cambridge Healthtech Institute’s CNS Disease Models brings together leading drug discovery and preclinical scientists to discuss the latest developments in animal models, induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESCs) for neurodegenerative, psychiatric and neurological disorders as well as the critical factors that affect the variability and reproducibility of these models.

Final Agenda

Tuesday, June 19

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

Essex North East

8:15 Chairperson’s Opening Remarks

Takaomi C. Saido, PhD, Laboratory Head, Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute

8:20 Single App Knock-In Mouse Models of Alzheimer’s Disease without Overexpression Artifacts for the Best R&D

Takaomi_SaidoTakaomi C. Saido, PhD, Laboratory Head, Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute

The conventional models of Alzheimer’s disease (AD) suffer from a number of artifacts such as endogenous gene locus destruction, presynaptic molecular crowding, sudden death, overproduction of non-A APP fragments, non-specific ER stress, non-specific calcium dysmetabolism, etc. The failure of more than 400 medication candidates in clinical trials is likely due to the use of inappropriate models for preclinical studies. Pros and cons of the conventional and new models will be described in detail.

8:50 MODEL-AD: Model Organism Development and Evaluation for Late Onset Alzheimer’s Disease

Mike_SasnerMichael Sasner, PhD, Co-Director, Disease Modeling Program, MODEL-AD Center

The MODEL-AD Center was established to generate translational models for late-onset AD. The goals of the Center are: to identify novel genetic variants, genes and biomarkers from AD patient data; to generate and validate new animal models based on these LOAD variants; and to utilize these novel models in a preclinical testing paradigm.

9:20 Selective in vivo Inhibition of β-arrestin Signaling in Alzheimer’s Disease

Amantha_ThathiahAmantha Thathiah, PhD, Assistant Professor, Department of Neurobiology, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine

G protein-coupled receptors (GPCRs) activate G protein and β-arrestin signaling to regulate distinct physiological functions. As such, development of G protein- and β-arrestin ligands, which modulate distinct signaling pathways, will provide novel opportunities for therapeutic intervention in Alzheimer’s disease in the absence of undesirable side effects. We will discuss development of a mouse model that is selectively uncoupled from β-arrestin 2 signaling, providing proof-of-concept for development of GPCR biased ligands.

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

Essex North East  

10:35 CT-526: A Peptide Targeting CDK5 in Neurodegenerative Disease

Kent_WernerKent Werner, MD, PhD, Co-Founder and CEO, Cogentis Therapeutics; Johns Hopkins Neurology Adjunct Faculty

In Alzheimer’s disease, CDK-5 is one of the two major kinases to phosphorylate tau and is found to be 10x more active than in cognitively normal controls - largely due to p25. Previous efforts to target CDK5 were toxic and unsuccessful. CT-526 is a peptide targeting p25 and exhibiting zero toxicity at 100x the effective dose. In multiple models, CT-526 reduces tau hyperphosphorylation, amyloid plaque formation, neuroinflammation and rescues phenotype.

11:05 Models of Amyloid Toxicity and Neural Stem Cell Plasticity in Adult Zebrafish and 3D Human Neural Progenitor Cell Cultures

Caghan_KizliCaghan Kizil, PhD, Helmholtz Young Investigator Group Leader, German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association

Neural progenitors constitute the endogenous reservoir for new neurons and can potentially be harnessed for regenerative therapies in neurodegenerative diseases. To elucidate the molecular programs that might endow regenerative potential to endogenous neural stem/progenitor cells, we have been developing novel in vivo and in vitro models in zebrafish and dissective 3D hydrogel cultures. The talk will focus on these comparative models and their use in biological and pre-clinical investigations.

11:35 High Content Behavioral Phenotyping and Machine Learning Approaches to AD Drug Discovery

Emer_LeahyEmer Leahy, PhD, President, CEO, PsychoGenics Inc.

Prevention/ reduction of pathology in AD models hasn’t translated to improved cognitive performance in patients. This advocates more refined assessment of behavioral effects of drugs in Alzheimer’s models. The talk will describe how high content, behavioral platforms, together with proprietary machine learning, can detect the phenotype of AD mouse models earlier and more robustly than standard testing. This approach offers opportunities to reinvigorate the drug discovery process by identifying compounds that reverse the AD phenotype.

12:05 Enjoy Lunch on Your Own

St. George CD     

1:15 Chairperson’s Remarks

Ibrahim Domian, MD, PhD, Assistant Physician, Massachusetts General Hospital, Assistant Professor of Medicine, Harvard Medical School

1:20 Leveraging Stem Cell Technology to Fuel Drug Discovery for Neurodegenerative Diseases

Carlo Cusulin, PhD, Senior Scientist, Disease Relevant Cellular Assays, Chemical Biology, F. Hoffmann-La Roche

Drug discovery for neurodegenerative diseases presents several challenges, because of the complexity of these disorders and the scarcity of reliable and translatable models. iPS technology offers the possibility to produce the relevant cell types (i.e., neurons, microglia, astrocytes) and introduce disease stimuli to obtain an in vitro system amenable for screening. We focused on generating models of Alzheimer’s disease, starting from patient-derived iPSCs and assessing the effect of disease-modifying compounds.

1:50 iPSC Derived Neurons and Microglia for in vitro Pharmacology

Johannes Grosse, PhD, Director, Neuroscience Drug Discovery/Alliances, Takeda

The discrepancy between the massive private and academic investments in drug discovery for neurological and psychiatric diseases and the small and still declining number in novel drug approvals is a clear indicator for the unique challenges of the field. Those have been identified at all phases of drug discovery from target validation and hypothesis via pre-clinical models for pharmacological tests to the design of clinical trials, use of biomarkers and regulatory affairs.

2:20 Advanced Physiologically Relevant hiPSC-Based Platforms for Drug Discovery

Fabian_ZanellaFabian Zanella, Director, Research & Development, StemoniX

We present human induced pluripotent stem cell (hiPSC)-based platforms which were structurally engineered with greater physiological relevance aimed to elevate performance in drug discovery applications. microBrain® 3D comprises cortical neural spheroids that feature high functionality with robust spontaneous activity and expected responses to established neuromodulators. microHeart® allows cardiomyocytes to adopt cell geometries and intercellular organization that resemble native heart tissue, translating into differential pharmacological response to known cardioactive compounds. 

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

3:30 Modeling Good Behavior: Is it Time to Raise the Bar on Pluripotent Stem Cell Derived Screening?

Sandra Engle, PhD, Associate Director, Translational Cellular Sciences, Stem Cells & Genomic Engineering, Biogen

Ten years after its introduction, iPSC technology has matured. We can now better maintain pluripotency and differentiate cells to desired phenotypes with a reproducibility and scale that makes them amenable to larger scale screening efforts. As iPSC-derived cells become a routine cell source for screening, we need to carefully consider how to use these cells to produce meaningful results. This talk will explore the current and future state of high through-put screening using iPSC-derived neural cells.

4:00 All-Optical Electrophysiology for Neuroscience Drug Discovery

Graham Dempsey, PhD, Vice President, Research and Development, Q-State Biosciences

Human induced pluripotent stem (iPS) cell-based models have become a powerful approach to disease phenotyping for drug discovery applications. We have created an optogenetic platform called Optopatch that rapidly and robustly characterizes the electrophysiological response of iPS cell-derived neurons. Our approach provides an information-rich readout of pharmacological changes in both intrinsic neuronal excitability and synaptic transmission with single-cell precision and dramatically improved throughput

4:30 PANEL DISCUSSION: iPSC-Based Neurodegenerative Disease Modeling

Moderator: Johannes Grosse, PhD, Director, Neuroscience Drug Discovery/Alliances, Takeda

Human neurodegenerative disorders are among the most difficult to study. This panel will discuss existing and future models for major neurodegenerative diseases.

  • How do we establish that phenotypes “in a dish” are relevant to the patient’s disease?
  • Does the relative immaturity of neurons in the dish matter and, if so, what do we do about it?
  • What are the major technical barriers to high-throughput screening of iPSc-derived neuronal models?
  • Does the technology circumvent the need for rodent preclinical neurodegenerative disease models?

Panelist: Carlo Cusulin, PhD, Senior Scientist, Disease Relevant Cellular Assays, Chemical Biology, F. Hoffmann-La Roche

Chee Yeun Chung, PhD, Scientific Co-Founder and Associate Director, Discovery Biology, Yumanity Therapeutics

Sandra Engle, PhD, Associate Director, Translational Cellular Sciences, Stem Cells & Genomic Engineering, Biogen

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.

The Suitability of Animal Models for Preclincal Studies

Caghan Kizil, PhD, Helmholtz Young Investigator Group Leader, German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association

  • What type of animal/experimental models are used for neurodegenerative disease models?
  • What limitations are there for experimental models?
  • How well can we recapitulate the diseases in experimental animal models?
  • How can humanized models be improved?
  • What is the future of research for CNS disease models?

Modeling Neurodegenerative Disorders for Drug Discovery and Development

Bilada Bilican, Ph.D., Investigator II, Neuroscience, Novartis Institutes for BioMedical Research(NIBR)

  • In vitro correlates of complex neurodegenerative diseases.
  • How to model apparently sporadic neurodegenerative disorders?
  • Advanced cellular models - how to address cell-autonomous vs non-cell autonomous mechanisms of neurodegeneration?
  • Phenotype- vs target-based drug screening

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)

St. George CD

8:25 Chairperson’s Remarks

Chee Yeun Chung, PhD, Scientific Co-Founder and Associate Director, Discovery Biology, Yumanity Therapeutics

8:30 Building a Robust Stem Cell-Based Discovery Platform for Neurodegenerative Diseases

Chee Yeun Chung, PhD, Scientific Co-Founder and Associate Director, Discovery Biology, Yumanity Therapeutics

Phenotypic screening in neurons and glia derived from patients is now conceivable through unprecedented developments in reprogramming, transdifferentiation, and genome editing. We outline progress in this nascent field, but also consider the formidable hurdles to identifying robust, disease-relevant and screenable cellular phenotypes in patient-derived cells. We illustrate how analysis in the simple baker’s yeast cell Saccharaomyces cerevisiae is driving discovery in patient-derived neurons, and how approaches in this model organism can establish a paradigm to guide the development of stem cell-based phenotypic screens.

9:00 Functionalization of Schizophrenia GWAS Variants by High-Throughput Differentiation of Human Induced Pluripotent Stem Cells

Bilada Bilican, PhD, Investigator II, Neuroscience, Novartis Institutes for BioMedical Research (NIBR)

Schizophrenia is a complex multifactorial and polygenic disorder, with both rare and common genetic variants contributing to disease risk. Genome-wide association studies (GWAS) have highlighted a large number of genetic variants with potential disease association, but validation and prioritization of risk genes remains a challenge.

9:30 Developing Relevant In Vitro CNS Models for Drug Discovery

Daniel_HaagDaniel Haag, PhD, CSO, NeuCyte, Inc.

NeuCyte Inc. is a biotechnology company focusing on early phases of CNS drug discovery. Based on our SynFireTM technology, we have developed a proprietary human neural in vitro platform for complex electrophysiological and morphological readouts suited for target identification and validation, efficacy testing and neurotoxicity assessment. Using patient-derived and genetically engineered defined neural cell types, NeuCyte builds unique cell-based assays for modelling neurological and neurodegenerative disorders.

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

St. George CD

10:45 A 3D Culture Model of Alzheimer’s Disease: Towards a Cure-in-a-Dish?

Doo Yeon Kim, PhD, Assistant Professor of Neurology, Genetics and Aging Research Unit, Massachusetts General Hospital / Harvard Medical School

Recently, we developed a novel 3D human neural culture model of Alzheimer’s disease (AD) that recapitulates key pathological markers of AD. In this presentation, I will show our recent progress including 1) improved 3D culture models based on single-clonal hNPCs and microfluidic devices, 2) mechanistic studies to dissect pathogenic cascades that lead to NFT and neuronal death, and 3) our efforts to optimize 3D culture models for mid-throughput AD drug screening against FDA-approved drugs.

11:15 Identification of Axon Growth Promoting Small Molecules Using a High Throughput Phenotypic Assay Exploiting HiPSC Derived Human Motor and Cortical Neurons

Bhagat Singh, PhD, Research Fellow, Neurobiology, Clifford Wolf’s Lab, Boston Children’s Hospital, Harvard Medical School

We have generated standardized protocols to differentiate motor and cortical neurons from hiPSCs and also have developed a robust, sensitive and reproducible phenotypic neurite outgrowth assay (Z’>0.5) that recapitulates CNS specific growth phenotypes in vitro. This provides us with a means to screen for regeneration-promoting compounds in a high throughput mode.

11:45 Session Break

11:50 Bridging Luncheon Presentation: Nuclear Imaging of Neuroinflammation in Rodent Models of Neurodegenerative Diseases

Tuulia_HuhtalaTuulia Huhtala, PhD, Head, Biomarkers and in vitro Biology, Discovery, Charles River

Activation of the mitochondrial translocator protein (TSPO) is linked to neuroinflammation, and TSPO ligands can be used for in vivo PET or SPECT imaging. In the current studies, we utilized these ligands to assess the extent of neuroinflammation after lipopolysaccharide (LPS) infusion, following induction of multiple sclerosis (MS) and neuropathic pain.

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

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,

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

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