Since their discovery/invention a little less than a decade ago, induced pluripotent stem (iPS) cells inspired hope to become a powerful tool for drug discovery and development applications. With advances in reprogramming and differentiation technologies,
as well as with the recent availability of gene editing approaches, we are finally able to create more complex and phenotypically accurate cellular models based on iPS cell technology. This opens new and exciting opportunities for iPS cell utilization
in early discovery, preclinical and translational research. Cambridge Healthtech Institute’s inaugural iPS Cell Technology in Drug Discovery and Development conference is designed to bring together experts and bench scientists working with iPS
cells and end users of their services, researchers working on finding cures for specific diseases and disorders.
Wednesday, June 15
7:00 am Registration and Morning Coffee
8:25 Chairperson’s Opening Remarks
Ulrich Broeckel, M.D., Professor of Pediatrics, Medicine and Physiology, Pediatrics, Medical College of Wisconsin
8:35 KEYNOTE PRESENTATION: iPS CELL TECHNOLOGY, GENE EDITING AND DISEASE RESEARCH
Rudolf Jaenisch, M.D., Founding Member, Whitehead Institute for Biomedical Research; Professor, Department of Biology, Massachusetts Institute of Technology
The development of the iPS cell technology has revolutionized our ability to study human diseases in defined in vitro cell culture systems. A major problem of using iPS cells for this “disease in the dish” approach is the choice of control
cells because of the unpredictable variability between different iPS / ES cells to differentiate into a given lineage. Recently developed efficient gene editing methods such as the CRISPR/Cas system allow the creation of genetically defined models
of monogenic as well as polygenic human disorders.
9:05 iPSC Genome Editing: From Modeling Disease to Novel Therapeutics
Chad Cowan, Ph.D., Associate Professor, Harvard Department of Stem Cell & Regenerative Biology (HSCRB)
Our goal is to understand how naturally occurring human genetic variation protects (or predisposes) some people to cardiovascular and metabolic disease—the leading cause of death in the world—and to use that information to develop therapies
that can protect the entire population from disease.
9:35 Stem Cells and Genome Editing to Enable Drug Discovery
Jeffrey Stock, Principal Scientist, Global R&D Groton Labs, Pfizer
Significant advances have been made in recent years in the isolation/generation and differentiation of human pluripotent stem cells (hPSC). Similarly, powerful tools for in vitro genomic editing are now readily available. When combined, these technologies
make it possible to generate physiologically relevant models of human disease to enable drug discovery. In this presentation, we provide some examples of how we have applied these technologies to produce models that are suitable for target validation
as well as small molecule screening.
10:05 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:50 Phenotypic Diversity in a Large Cohort of iPSC-Derived Cardiomyocytes as a Platform for Response Modeling in Drug Development
Ulrich Broeckel, M.D., Professor of Pediatrics, Medicine and Physiology, Pediatrics, Medical
College of Wisconsin
We will discuss the underlying concepts of phenotypic variation and the impact of genomic variation on common, complex phenotypes in iPSCs. To demonstrate this, we have established 250 iPSC cell lines from the NHLBI HyperGen study. We will discuss
our approach to analyzing disease phenotypes on a molecular level using iPSC-derived cardiomyocytes. Furthermore we will present data, which provides a framework to use the obtained data for the selection of samples for compound screening and
11:20 Transcriptional and Proteomic Profiling of Human Pluripotent Stem Cell-Derived Motor Neurons: Implications for Familial Amyotrophic Lateral Sclerosis
Joseph Klim, Ph.D., Postdoctoral Scholar, Eggan Lab, Stem Cell and Regenerative Biology Department, Harvard
We combined pluripotent stem cell technologies with both RNA sequencing and mass spectrometry-based proteomics to map alterations to mRNA and protein levels in motor neurons expressing mutant SOD1. This approach enabled us to study the effects of
mutant SOD1 in purified populations of motor neurons using multiple molecular metrics over time. These investigations have afforded an unprecedented glimpse at the biochemical make-up of human stem cell-derived motor neurons and how they change
11:50 3D Spheroids for Cardiovascular Drug Discovery in Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Yoko Ejiri, Researcher, Microdevice Team, New Business Development Division, Kuraray Co. Ltd.
This Elplasia® 3D spheroid cell culture study tested whether human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) system could improve on industry-standard preclinical cardiotoxicity screening methods, and identify
the effects of well-characterized drugs. With Elplasia brands of Kuraray you can screen more compounds earlier in cardiovascular drug discovery.
12:05 Selected Poster Presentations
12:25 pm Enjoy Lunch On Your Own
1:40 Chairperson’s Remarks
Vikram Khurana, M.D., Co-Founder and Vice President, Discovery Technologies, Yumanity Therapeutics
1:50 High-Throughput Phenotyping of Human PSC Derived Neurons
Bilada Bilican, Ph.D., Investigator II, Neuroscience, Novartis Institutes for BioMedical
We established a fully automated human pluripotent stem cell (PSC) maintenance and excitatory cortical neuronal differentiation platform that enables parallel phenotyping of many different lines at once. This human disease-modeling platform
is being integrated into Novartis’ lead discovery pipeline to identify new targets, molecules, and to elucidate cellular aspects of human neuronal biology.
2:20 Modeling ALS with Patient Specific iPSCs
Shila Mekhoubad, Ph.D., Scientist, Stem Cell Biology Lab, Biogen
Advances in stem cell biology and neuronal differentiations have provided a new platform to study ALS in vitro. Here we will describe our use of induced pluripotent stem cells (iPSCs) from patients with familial ALS to establish new models
and tools that can contribute to the development and validation of novel ALS therapeutics.
2:50 Refreshment Break in the Exhibit Hall with Poster Viewing
3:35 Modeling Huntington’s Disease in IPS Cells: Development and Validation of Phenotypes Relevant for Disease
Kimberly B. Kegel-Gleason, Ph.D., Assistant Professor in Neurology,
Massachusetts General Hospital & Harvard Medical School
Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG expansion in the HD gene. Using induced pluripotent stem (IPS) cells from controls and HD patients with low and medium CAG repeat expansions, we are developing
assays for target validation and drug discovery based on phenotypic changes observed in PI 3-kinase dependent signaling, Rac activation and cell motility in microfluidic channels.
4:05 From Yeast to Patient iPS Cells: A Drug Discovery Pipeline for Neurodegeneration
Vikram Khurana, M.D., Co-Founder and Vice President, Discovery Technologies, Yumanity
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.
4:35 PANEL DISCUSSION: iPSC-Based Neurodegenerative Disease Modeling
Vikram Khurana, M.D., Co-Founder and Vice President, Discovery Technologies, Yumanity Therapeutics
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?
5:35 Welcome Reception in the Exhibit Hall with Poster Viewing
6:45 Close of Day
Thursday, June 16
7:00 am Registration.
7:30 Interactive Breakout Discussion Groups with Continental Breakfast
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. Continental breakfast is available for all participants.
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
iPS Cell Technology Enabled Organ-on-Chip Models
James Hickman, Ph.D., Professor, NanoScience Technology Center, University of Central Florida
- Disease models
- 2D vs 3D models
- Main applications
Gene Editing in iPS Cells: Technology and Major Applications
Joseph Klim Ph.D., Postdoctoral Scholar, Eggan Lab, Stem Cell
and Regenerative Biology Department
- CRISPR/Cas 9 technologies have opened the door to changing the basic code of the genome, but other reported uses include specific modulation of gene expression and directed epigenetic modifications. What experience does the group have
with genome editing in iPS cells and does anyone have experience applying these other uses to pluripotent stem cells.
- One promisng use of genome that has been touted is the ability to generate reporter lines to identify and purify cells of interest from heterogenous mixtures. To date, there have been very few examples of reporter cell lines generated
through genome editing. What is the group’s experiences with generating reporter lines using gene editing either successfully or unsuccessfully?
- There are advantages and disadvantages to editing the genome in stem cells vs the differentiated, cell types of interest. What are experiences or tools within the group for editing in differentiated cell types?
8:35 Chairperson’s Remarks
James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida
8:45 Utilization of iPSCs in Developing Human-on-a-Chip Systems for Phenotypic Screening Applications
James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor,
Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida
Our lab is developing multi-organ human-on-a-chip systems for evaluating toxicity and efficacy compounds for drug discovery applications. Validation of the systems has already indicated good agreement with previous literature values, which
gauges well for the predictive power of these platforms. Applications for neurodegenerative diseases, metabolic disorders as well as cardiac and muscle deficiencies will be highlighted in the talk.
9:15 Human-Induced Pluripotent Stem Cells Recapitulate Breast Cancer Patients’ Predilection to Doxorubicin-Induced Cardiotoxicity
Paul W. Burridge, Ph.D., Assistant Professor, Department of Pharmacology, Center for Pharmacogenomics,
Northwestern University Feinberg School of Medicine
The ability to predict which patients are likely to experience cardiotoxicity as a result of their chemotherapy represents a powerful clinical tool to attenuate this devastating side-effect. We report our progress towards this aim using the
hiPSC cell model, a battery of in vitro assays, and machine learning.
9:45 Utilization of Induced Pluripotent Stem Cells to Understand Tyrosine Kinase Inhibitors (TKIs)-Induced Hepatotoxicity
Qiang Shi, Ph.D., Principal Investigator, Division of Systems Biology, National Center for Toxicological Research (NCTR), U.S. FDA
For cancer patients, the benefits of anti-cancer agents are often countered by hepatotoxicity. The purpose of current study is to predict tyrosine kinase inhibitors (TKIs)-induced toxicity using rat primary hepatocytes and human induced pluripotent
stem cell (iPSC) -derived hepatocytes. Multi-parameter cellular endpoints have been used to examine the utilization of iPSC in safety screening. Data on cross-species comparison from rodent to human will be presented.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing
10:55 Chairperson’s Remarks
Joseph Klim, Ph.D., Postdoctoral Scholar, Eggan Lab, Stem Cell and Regenerative Biology Department, Harvard University
11:00 KEYNOTE PRESENTATION: STEM CELL PROGRAMMING AND REPROGRAMMING, AND APPLICATIONS OF iPSC TECHNOLOGIES TO MODELING OF THE NEUROMUSCULAR SYSTEM AND THE DISEASES THAT AFFECT IT
Kevin C. Eggan, Ph.D., Harvard Department of Stem Cell and Regenerative Biology, Howard Hughes
While iPSCs have created unprecedented opportunities for drug discovery, there remains uncertainty concerning the path to the clinic for candidate therapeutics discovered with their use. Here we share lessons that we learned, and believe
are generalizable to similar efforts, while taking a discovery made using iPSCs into a clinical trial.
11:30 Trans-Amniotic Stem Cell Therapy (TRASCET) for the Treatment of Birth Defects
Dario O. Fauza, M.D., Ph.D., Associate in Surgery, Boston Children's Hospital; Associate Professor,
Surgery, Harvard Medical School
Trans-Amniotic Stem Cell Therapy (TRASCET) is a novel therapeutic paradigm for the treatment of birth defects. It is based on the principle of harnessing/enhancing the normal biological role of amniotic fluid-derived mesenchymal stem cells
(afMSCs) for therapeutic benefit. The intra-amniotic delivery of afMSCs in large numbers can either elicit the repair, or significantly mitigate the effects associated with major congenital anomalies such as neural tube and abdominal wall
12:00 pm Enjoy Lunch on Your Own
1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing
1:45 PLENARY KEYNOTE SESSION
3:30 Refreshment Break in the Exhibit Hall with Poster Viewing
4:15 Close of Conference