Disease models continue to be developed and routinely used in drug discovery for understanding cellular pathways, identifying potential drug targets, and optimizing candidates for lead development. However, translation, reliability and predictability of data obtained in the past using these models remained questionable. Developing and utilizing new and relevant disease models has become imperative for better target validation and lead optimization. Cambridge Healthtech Institute’s inaugural symposium on New Tools for Disease Modeling features a series of talks given by experts who are using innovative ways to create and use disease models in vitro, ex vivo, in vivo and in silico. What are some of the approaches being used to develop these new models? How are they being used, and how reliable and predictable is the data when impacting decisions? Hear experiences and viewpoints shared by experts and join the interactive discussions during the symposium for active networking, brainstorming and collaborating.

Who should attend: Drug discovery scientists, cell biologists, stem cell biologists, computational scientists, scientists in functional screening, translational research, biomarker discovery

Monday, June 12

7:30 am Registration Open and Morning Coffee

EXPLORING RELEVANT IN VITRO AND IN VIVO MODELS

8:30 Chairperson’s Opening Remarks

James J. Hickman, Ph.D., Professor, Nanoscience Technology, Chemistry, Biomolecular Science, and Electrical Engineering, University of Central Florida

8:40 A Human Model of Neuromuscular Junction Activity for Investigating ALS and Other Neurological Diseases

James J. Hickman, Ph.D., Professor, Nanoscience Technology, Chemistry, Biomolecular Science, and Electrical Engineering, University of Central Florida

There is a lack of good models for neurodegenerative diseases, for efficacy and side effect determination during the drug discovery process. Our advances in culturing human stem cell derived neurons, astrocytes, muscle and Schwann cells in a defined serum-free medium, and integrating them with MEMS devices containing interactive functional multi-component systems is unique. The ability to differentiate the cells from iPSCs derived from patients offers potential for answering questions using functional human-on-a-chip systems.

9:10 An ex vivo Tumor Model Identifies Clinically Relevant Anticancer Therapies

Geoffrey Bartholomeusz, Ph.D., Associate Professor and Director, Target Identification and Validation Program, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center

We have developed an ex vivo tumor array for less expensive and faster drug development with PDX screening systems. The ex vivo tumors are similar in morphology and expression of biomarkers to the original PDX tumor and replicate the response profile of a panel of drugs tested in a PDX system. Our long-term goal is to incorporate our system into the clinical management of cancer to rapidly and cost-effectively identify patient-specific therapies.

9:40 Genetic and Non-Genetic Cardiomyopathies in Engineered Human Heart Muscle

Malte Tiburcy, M.D., Research Fellow, Institute of Pharmacology and Toxicology, University Medical Center Goettingen

Patient-specific and genetically modified pluripotent stem cells (iPSC) offer novel experimental approaches for studying human cells and disease-specific phenotypes in vitro with the prospect of making high fidelity predictions on therapeutic strategies in vivo. We provide evidence that organotypic tissue models like Engineered Heart Muscle (EHM) are instrumental in recapitulating pathophysiology of cardiac disease phenotypes. EHM may fill the gap between classical cell biology in vitro and physiological organ function in vivo.

10:10 Coffee Break

10:40 Modeling Cystic Fibrosis and Cachexia in Drosophila

Norbert Perrimon, Ph.D., Professor, Department of Genetics, Harvard Medical School

I will discuss two examples illustrating the power of Drosophila to model human diseases. First, through our studies on gut tumors, I will describe a model to dissect mechanisms involved in cachexia (Kwon et al., Dev Cell 2015). Second, I will present our data on ENaC showing that the intestine can be used as a model for Cystic Fibrosis (Kim et al., Dev Cell 2017).

11:10 TECHNOLOGY FORUM: Overcoming Challenges with Developing and Using New Tools for Disease Modeling

Moderator: James J. Hickman, Ph.D., Professor, Nanoscience Technology, Chemistry, Biomolecular Science, and Electrical Engineering, University of Central Florida

Participants: Speakers and Experts from Sponsoring Companies (Opportunity Available)

Investigators come together with service providers to discuss gaps in know-how and technology. They discuss current challenges and ways to work together to bring forth new assays, models, and analysis tools for disease modeling.

11:40 pm Sponsored Presentation (Opportunity Available)

12:10 Enjoy Lunch on Your Own

LEVERAGING IN SILICO TOOLS FOR BETTER CLINICAL TRANSLATION

1:40 Chairperson’s Remarks

Chengzu Long, Ph.D., Assistant Professor, Division of Cardiology, New York University School of Medicine

1:50 Network Medicine: Cellular Networks and Human Disease

Amitabh Sharma, Ph.D., Assistant Professor, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School

The emerging field of network medicine offers a platform to discover not only the molecular complexity of a particular disease, leading to the identification of disease modules and associated molecular mechanisms but also the molecular relationships among distinct phenotypes. Recent studies have exploited the information contained within protein interaction networks (Interactome) to disclose some of the molecular mechanisms underlying complex pathobiological processes. This suggests that both interactions and networks could emerge as a new class of targetable entities.

2:20 Preclinical to Clinical Translation in Oncology Using Mathematical Modeling

Andy Zhu, Ph.D., Senior Manager, Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International

Immune-deficient mice transplanted with subcutaneous tumors (xenografts) are routinely used to evaluate the efficacy of anti-tumor drug candidates pre-clinically. However, there are extensive debates about the clinical relevance of these models and whether they adequately predict clinical anti-tumor activity. This presentation will discuss the utility of pharmacokinetics and pharmacodynamics modeling for facilitating the preclinical to clinical translation of anti-tumor drug candidates.

2:50 Disease Tracking in Preclinical Studies of Cancer: More New Tools, the Same Old Issues

Chi-Ping Day, Ph.D., Staff Scientist, Cancer Modeling Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health

Incorporation of clinical relevant parameters into preclinical cancer studies requires disease tracking. Recent technological advances, including imaging methods and genetically engineered animals, have rendered real-time and/or long-term tracking more feasible in small animals. We will discuss the application of these new tools in preclinical modeling, as well as cancer growth kinetics required for guiding the evaluation of study outcomes and their clinical translation.

3:20 Refreshment Break

3:50 Genome Editing of Patient-Specific iPSCs to Model Cardiac Disease

Nazish Sayed, M.D., Ph.D., Instructor, Cardiovascular Institute, Stanford University School of Medicine

The mechanisms that underlie “cardiolaminopathy” remain elusive. Although LMNA mutations are known to induce endothelial-dysfunction, little is known about the EC-specific phenotype. Our data shows that iPSC-ECs derived from LMNA-mutated patients exhibit decreased EC functionality. Genome-editing of iPSCs enabled us to recapitulate the EC-disease phenotype to dissect the effects of LMNA mutations. This study is a first step towards understanding cardiolaminopathy by modeling endothelial-dysfunction.

4:20 Correction of Duchenne Muscular Dystrophy in Humanized Mouse Models by CRISPR-Mediated Genome Editing

Chengzu Long, Ph.D., Assistant Professor, Division of Cardiology, New York University School of Medicine

Previously, we used genome editing to correct the DMD mutation in mdx mice, a model for Duchenne muscular dystrophy (DMD). However, correction of the point mutation in mice does not fully address whether it is applicable across the heterogeneous spectrum of mutations in humans. To address this challenge, we are generating “humanized” mouse models of DMD by introducing the human mutations into the mouse DMD locus.

4:50 KEYNOTE PRESENTATION: Pitfalls and Promise of Using Human Stem Cells for Studying Disease

Kevin C. Eggan, Ph.D., Harvard Department of Stem Cell and Regenerative Biology, Director of Stem Cell Biology, Stanley Center for Psychiatric Research at the Broad Institute

The discovery of human ES and iPS cells now makes it principally possible to produce a limitless quantity of diverse cell types for the study of disease. I will describe both success stories and challenges encountered during our efforts to implement these strategies in the context of studying developmental and degenerative disorders of the nervous system.

5:20 Close of Symposium

6:30 Dinner Short Course Registration