iForum meetings provide a unique opportunity to connect with thought leaders from academia, government, biotech, and pharma to discover new applications and innovative uses for differentiated iPS cells through interactive, data-driven presentations.
Registration has closed for this multi-session meeting. Innovators from leading pharmaceutical, biotechnology, and academic institutions will be presenting data showing how human iPSC-derived technologies are fueling their research.
|September 14 – 16, 2015|
| Palmer House®, A Hilton Hotel |
17 E Monroe St
- Kapil Bharti, PhD, National Eye Institute – NIH
Disease Modeling & Drug Discovery
- Anne Bang, PhD, Sanford-Burnham Medical Research Institute
- Eileen Dolan, PhD, University of Chicago
- Cashell Jaquish, PhD, National Heart, Lung, and Blood Institute – NIH
- Evangelos Kiskinis, PhD, Northwestern University
- Jason Maynes, MD, PhD, The Hospital for Sick Children
- Rita Perlingeiro, PhD, University of Minnesota
- Fabian Grimm, PhD, Texas A&M University
- John Imredy, PhD, Merck & Co.
- Seiichi Ishida, PhD, National Institute of Health Sciences Japan
- Milica Radisic, PhD, University of Toronto
- Karin Staflin, PhD, Genentech
- Kohei Sawada, PhD, Eisai Co, Ltd
Tissue Engineering & Regenerative Medicine
- Eric Adler, MD, University of California–San Diego
- Bill Murphy, PhD, University of Wisconsin-Madison
- Dustin Wakeman, PhD, Rush University
- Jason Wertheim, MD, PhD, Northwestern University
Monday, September 14
|6:00 - 8:00 pm||Welcome Reception|
Tuesday, September 15
|7:00 am||Breakfast, Poster Setup, Exhibit Setup|
|8:00 am||Welcome |
Chris Parker, Vice President and Chief Commercial Officer, Cellular Dynamics International
|8:30 am||Induced to Cure: Developing an Autologous iPS Cell-derived RPE-based Cell Therapy for Macular Degeneration |
Kapil Bharti, PhD, NIH National Eye Institute
The recent success with embryonic stem (ES) cell-derived retinal pigment epithelium (RPE) has provided hope for a cure for degenerative eye diseases. Induced pluripotent stem (iPS) cells are an autologous source of stem cells potentially with fewer immune-challenges as compared to ES cells. Using a developmentally guided differentiation protocol, in collaboration with CDI, we have developed a completely xeno-free GLP-grade protocol to manufacture fully polarized RPE tissue from patient-specific iPS cells. The RPE monolayer along with its secreted ECM and a degradable scaffold forms a tissue that mimics the native tissue in structural and functional properties. We have begun Phase I IND-enabling studies with the goal to transplant autologous iPS cell-derived RPE in patients in advanced Geographic Atrophy stage of age-related macular degeneration (AMD), one of the leading blinding diseases in the US. Our work will provide a potential personalized cell therapy for AMD patients.
Session 1: Tissue Engineering & Regenerative Medicine
|9:30 am||Biomaterials for Assembly of Stem Cell-derived Human Tissues |
Bill Murphy (Session Chairperson), PhD, University of Wisconsin-Madison
The need for human, organotypic culture models coupled with the requirements of contemporary drug discovery and toxin screening (i.e. reproducibility, high throughput, transferability of data, and clear mechanisms of action) frame an opportunity for a paradigm shift. The next generation of high throughput cell-based assay formats will require a broadly applicable set of tools for human tissue assembly and analysis. Toward that end, we have recently focused on: i) generating iPSC-derived cells that properly represent the diverse phenotypic characteristics of developing or mature human somatic cells; ii) assembling organotypic cell culture systems that are robust and reproducible; iii) translating organotypic cell culture models to microscale systems for high throughput screening; and iv) combining genomic analyses with bioinformatics to gain insights into organotypic model assembly and the pathways influenced by drugs and toxins. This talk will emphasize recent studies in which we have explored biologically driven assembly of organotypic vascular and neural tissues. These tissues mimic critical aspects of human tissues and can be used for predictive neurodevelopmental toxicity and for discovery of vascular disrupting compounds.
|10:00 am||Poster Teasers: Tissue Engineering & Regenerative Medicine|
|10:15 am||Refreshments, Poster Session, Exhibits|
|11:00 am||iPSC-derived Cardiomyocytes from Patients with LAMP-2 Mutations Reveal Key Insights into the Pathogenesis of Danon Disease |
Eric Adler, MD, University of California-San Diego
The focus of our lab is the use of pluripotent stem cells for the study and treatment of cardiovascular disease. In our previous studies, we demonstrated that these cells retain the essential phenotypic features of the patients from which they were derived. Our recent work has focused on the use of these cardiomyocytes to study cardiac metabolism, and in particular Danon disease. Using Danon disease cardiomyocytes, we have confirmed that dysfunctional autophagy is central to the pathogenesis of disease, and ultimately leads to markedly impaired energetics and excessive apoptosis. We have also used these cells to develop high throughput assays for the identification of small molecules that may be suitable therapeutics for Danon disease patients.
|11:30 am||Sponsor Presentation|
|12:00 pm||Exploring the Therapeutic Value of Cryopreserved iPSC-derived Midbrain Dopamine Neurons for Parkinson's Disease |
Dustin Wakeman, PhD, Rush University
Cryopreservation of post-mitotic, induced pluripotent stem cell-derived midbrain lineage dopamine neurons (iPSC-mDA) is a significant advancement for cell therapy in Parkinson’s disease. Here, we demonstrate that cryopreserved iPSC-mDA neurons are reliably thawed with excellent viability and maintain biochemical and physiological signatures indicative of human midbrain dopamine neurons. Furthermore, we examined the engraftment potential of iPSC-mDA neurons after transplantation into both the rodent and nonhuman primate brain. Immunohistochemical analysis demonstrated robust graft survival and maintenance of the midbrain dopaminergic phenotype with extensive fiber innervation into the host. Furthermore, we found no evidence of cell proliferation, indicating safety in our initial studies. Long-term functional studies are underway to ascertain whether cryopreserved iPSC-mDA neurons will provide functional benefit in the 6-OHDA-lesioned rat and MPTP-lesioned nonhuman primate models of Parkinson’s disease. These results indicate considerable promise for the development of pluripotent cell-based therapies in Parkinson’s disease.
|12:30 pm||Lunch, Roundtable Discussions, Poster Session, Exhibits|
Session 2: Toxicity
|1:45 pm||John Imredy (Session Chairperson), PhD, Merck & Co., Inc.|
|2:15 pm||Contribution of Human iPS Cell-derived Hepatocytes to Drug Safety Tests |
Seiichi Ishida, PhD, National Institute of Health Sciences
Hepatotoxicity evaluation of drug candidates at early stages of the development process is one of the indispensable tests to secure their safety in human administration. Human primary hepatocytes are mainly used for this purpose, but inherited in the problems caused by their inter-individual variations and limited supply. Hepatocyte-like cells derived from human iPS cells (hiPSC-hepatocytes) are expected as an alternative cell source to primary hepatocytes. To clarify their applicability to the pharmacokinetic studies, we have been evaluating commercially available hiPSC-hepatocyte functionality. We measured metabolic activities and mRNA expressions of several CYPs and evaluated inducibility of CYP1A2, CYP2B6, and CYP3A4 by typical inducers. The enzymatic activities, gene expressions, and inductions have been drastically improved during the last two years. Draft proposal for an OECD new performance-based test guideline (PBTG) "Human cytochrome P450 (CYP) n-fold induction in vitro test method" is now in preparation by ECVAM; thus, the contribution of hiPSC-hepatocytes to this PBTG will be discussed.
|2:45 pm||Multidimensional Toxicity Profiling in Induced Pluripotent Stem Cell-derived Cardiomyocytes and Hepatocytes |
Fabian Grimm, PhD, Texas A&M University
Cell-based high content screening (HCS) assays are becoming an increasingly attractive alternative to traditional in vitro and in vivo approaches in toxicological safety assessment and pharmaceutical drug development. The time- and cost-effectiveness of multidimensional HCS technologies combined with the application of novel organotypic cell culture models, i.e. induced human pluripotent stem cell (iPSC)-derived cells, open new opportunities to employ physiologically relevant in vitro systems to improve screening for potential chemical hazards. In this study, we utilized two human iPSC-derived cell types, cardiomyocytes and hepatocytes, to test various high content and molecular assay combinations, including cardiophysiology measurements and high content cellular imaging, for their applicability in a multiparametric screening format. In addition, we demonstrate that such combinatorial screening approaches represent a viable strategy for toxicity profiling and predictive safety assessment of complex chemicals, such as refined petroleum substances.
|3:15 pm||Poster Teasers: Toxicity|
|3:30 pm||Refreshments, Poster Session, Exhibits|
|4:15 pm||Use of iCell Neurons to Investigate Neuronal Toxicity |
Karin Staflin, PhD, Genentech
Neurotoxicity is a major cause of therapeutic attrition from the drug development process, and neurologic safety issues rank among the highest for adverse drug reaction related withdrawals, along with hepatotoxicity and cardiotoxicity. It is imperative to develop useful preclinical tools to assess the potential for neurotoxicity early in drug development and minimize clinical risk to patients. These in vitro assays can run ahead of in vivo animal studies and augment those studies with data in the most relevant species before clinical trials begin. Recently, significant progress has been made, both in availability of reagents (e.g. stem cell-derived human neurons) as well as technologies (e.g. MEA, high content imaging) to assess function. These advances have made it possible to query the function of neurons on a higher throughput and longer term basis and in an integrated manner in the species of relevance (human). For this purpose, we have characterized iCell Neurons for their semblance to human neuronal tissues and developed a model for assessing neurotoxicity potential in vitro. These characterizations, some preliminary data, and potential to impact current neurotoxicity assessment paradigms will be discussed in this talk.
|4:45 pm||A Novel Method for the Assessment of Cardiotoxicity by Multi-spheroid Imaging Analysis of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes |
Kohei Sawada, PhD, Eisai Co., Ltd.
|5:15 pm||Human Biowires and Injectable Tissues |
Milica Radisic, PhD, University of Toronto
Engineering effective therapies for heart disease will require restoration of beating myocardium as well as revascularization of the injured or impaired area. Since human postnatal cardiomyocytes are terminally differentiated, it is not possible to obtain these cells and expand them from biopsies of primary tissue. Recent advances in stem cell biology and development of directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSC). However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium suitable for drug testing or restoration of adult hearts. We developed a new platform that combines 3-dimensional cell cultivation in a microfabricated system with electrical stimulation to mature hPSC-derived cardiac tissues. We utilized quantitative structural, molecular and electrophysiological analyses to elucidate the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allowed for the generation of 3-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation markedly increased myofibril ultrastructural organization, displayed elevated conduction velocity and altered both the electrophysiological and calcium handling properties versus non-stimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate. The biowires were further engineered into a completely plastic and inert platform, exhibiting a positive force-frequency relationship and physiological responses to isoproterenol and E4031. The new platform enables simultaneous mapping of force and Ca2+ transients from a single tissue. We will also discuss approaches to vascularizing cardiac tissue by development of new perfusable microfabricated scaffolds, termed AngioChips, that are also suitable for engineering a human body on a chip. Lastly, placing a functional, beating, cardiac patch onto the heart currently requires opening of the chest. We will discuss shape-memory scaffolds that enable a minimally invasive delivery of engineered tissues in vivo.
|6:00 - 10:00 pm||Dinner & Social Event|
Wednesday, September 16
|7:00 am||Breakfast, Poster Session, Exhibits|
|8:00 am||Opening Remarks|
Session 3: Disease Modeling & Drug Discovery
|8:30 am||The Next Generation Genetic Association Study (Next Gen): Using iPSCs to Model Functional Genomics of Common Disease |
Cashell Jaquish (Session Chairperson), PhD, NIH National Heart, Lung, and Blood Institute
The NHLBI and NHGRI have partnered to support a novel, large scale program to utilize induced pluripotent stem cells to model “disease in a dish” for common diseases. The 5 year program began in 2011 and has generated iPSCs from 1,500 patients with known genotypes and phenotypes across 9 studies. The program has generated a valuable resource for the scientific community and has used the cells to test specific hypotheses regarding gene function for a variety of phenotypes, such as left ventricular hypertrophy, sickle cell disease, dyslipidemia, CHD, pulmonary hypertension, insulin metabolism, electrophysiology and coagulation phenotypes. The program consists of technology development, resource development and scientific hypothesis testing with the goal of building upon existing genomic findings to add functional information by assessing cellular profiles that are surrogates for disease phenotypes. The resource consists of well-characterized cell lines from diverse ethnicities and age ranges from cases and controls. The cells will be housed and made available by WiCell. A brief discussion of the goals of the program and an update on progress and discussion of the resource and its uses will be presented.
|9:00 am||Phenotypic Screening with hiPSC-derived Cardiomyocytes and Neurons |
Anne Bang, PhD, Sanford Burnham Prebys Medical Discovery Institute
Screens for small molecules that modulate a cellular phenotype, known as “phenotypic screens,” interrogate all components and pathways of the cell and not just a single target, an approach that has been remarkably effective at producing drug candidates. A major strength of combining phenotypic drug screening with hiPSC-derived cells is relevance and an increased probability that activity in such assays might be translated into therapeutic effects. Development of technology platforms to perform phenotypic screens of hiPSC with relatively high throughput will be essential to realize their potential for disease modeling and drug discovery. Towards this goal, we have been working to develop a standardized battery of assays against which hiPSC-derived neurons and cardiomyocytes can be screened for specific phenotypes. We will discuss our screening results and development of hiPSC-based models for testing of drugs on disease relevant cell types.
|9:30 am||Sponsor Presentation|
|10:00 am||Poster Teasers: Disease Modeling & Drug Discovery|
|10:15 am||Refreshments, Poster Session, Exhibits|
|11:00 am||Incorporating Stem Cell Technology in Pharmacogenomic Studies |
M. Eileen Dolan, PhD, University of Chicago
Greater understanding of the molecular pathogenesis of CIPN has been impeded by the lack of clinically relevant models, slowing the discovery of impactful drug targets. The use of differentiated cell types from induced pluripotent stem cell (iPSCs) is likely to revolutionize the field. We have optimized conditions to utilize stem cell-derived neurons as a model to evaluate the effects of mechanistically distinct chemotherapeutic drugs and the effects of cellular sensitivity to chemotherapeutics following knockdown of specific genes. As a testament to the utility of the model for studies of neuropathy, we observed that genes involved in neuropathy had relatively higher expression levels in these samples across different time points. Our results also suggest that the process used to differentiate iPSCs into neurons results in consistent neurons as measured by RNA-seq and sensitivity to drugs. Therefore, this model is reasonable for studies of human neuropathy, druggable targets to prevent neuropathy as well as pharmacogenomic studies for drug-induced neuropathy.
|11:30 am||From iPS Cells to Skeletal Muscle Precursors: Potential for Gene Correction and Therapeutic Application in LGMD2I |
Rita Perlingeiro, PhD, University of Minnesota
A major obstacle in the application of cell-based therapies for the treatment of neuromuscular disorders is obtaining the appropriate number of stem/progenitor cells to produce effective engraftment. The use of pluripotent embryonic stem (ES) or induced pluripotent stem (iPS) cells could overcome this hurdle. We have developed a method to efficiently generate skeletal myogenic progenitors from pluripotent stem cells through Pax3 or Pax7 induction. We have applied this method to mouse and human ES and iPS cells. In each case, transplantation of pluripotent-derived skeletal myogenic progenitor cells into dystrophic mice provides both extensive and long-term muscle regeneration that result in improved muscle function. During this talk, I will be discussing our recent results on the systemic transplantation of pluripotent-derived skeletal myogenic progenitors and their implications for therapeutic applications. I will also be covering our new developments on iPS cells, their potential for gene correction, modeling disease, and therapeutic application.
|12:00 pm||Lunch, Roundtable Discussions|
|1:00 pm||Dessert, Poster Session, Exhibits|
|1:30 pm||Modeling Human Cardiac Disease and the Design of Novel Therapeutics Based on Force Transduction |
Jason Maynes, MD, PhD, The Hospital for Sick Children
Heart failure is the leading cause of death and disability in North America. Current therapies do not address the underlying mechanisms of cardiac dysfunction, primarily treating disease symptoms. We have shown that the protein integrin-linked kinase (ILK) is down-regulated in heart failure and how activation of ILK can correct the phenotype associated with both genetic and drug-induced cardiac dysfunction. ILK activity improves calcium regulation in the cardiomyocyte, improving contractility and rhythm generation, through direct interaction with the cardiac calcium pump SERCA-2a. Our data illustrates how activation of ILK can be used as a novel, mechanism-based therapy for heart failure.
|2:00 pm||Probing Disease Mechanisms in ALS & Dravet Syndrome Using iPSCs, Reprogramming and Optogenetic Approaches |
Evangelos Kiskinis, PhD, Northwestern University
The lack of easy accessibility to the cells of the nervous system has hampered progress towards the discovery of degenerative mechanisms as well as more effective treatments for neurological diseases. The groundbreaking technology of reprogramming, which allows for the generation of patient-specific induced pluripotent stem cells (iPSCs), has created an unprecedented opportunity for a new approach towards developing cellular models of human disease. We employ this approach to generate cortical excitatory and inhibitory neurons as well as spinal motor neurons and astrocytes from individual patients. We use gene-editing techniques to introduce or fix mutations and then study the neurons we make by classical methods including immunocytochemistry, biochemistry, global genomic analysis, live cell imaging as well as by non-invasive electrophysiological recording techniques. During this talk, I will present our progress towards developing models of motor neuron disease as well as of Dravet Syndrome, a pediatric form of epilepsy.
|2:30 pm||Enhanced Biofunctionality and Phenotypic Maturation of iCell Hepatocytes on 3D Scaffolds |
Jason Wertheim, PhD, Northwestern University
iCell Hepatocytes may be used to model diseases and evaluate the toxicology profile of pharmaceutical agents ex vivo. We developed an extracellular matrix (ECM) scaffold and a second hybrid scaffold comprised of bio-plotted poly-L-lactide acid and infused with Type I collagen. iCell Hepatocytes cultured on these scaffolds were compared to control collagen coated plates with Matrigel overlay. iCell Hepatocytes grown within ECM scaffolds exhibited higher transcription of P450 enzymes as well as higher functional activity, which were significantly elevated compared to poly-L-lactide-collagen or Matrigel sandwich control cultures. Increased synthesis of albumin and decreased production of AFP suggested maturation of iCell Hepatocytes within ECM scaffolds. Taken together, growth of iCell Hepatocytes in ECM leads to increased biofunctionality of key phenotypic traits of hepatocyte like cells.
|3:00 pm||Final Remarks|
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Step into the lobby of Palmer House® A Hilton Hotel and gaze at the famous frescoed ceiling of this landmark Chicago, Illinois hotel. This AAA four-diamond-rated hotel has been hosting visitors to the Chicago Loop for over 140 years. Today, Palmer House Hilton continues to thrive in the heart of the theatre and financial district, just steps from the Art Institute, Millennium Park and State Street shopping. A short walk away is Grant Park, where summer festivals take place. Family attractions such as the Chicago Children’s Museum and Navy Pier are just a quick cab ride away.
Enjoy comfort and elegance in your guest room or suite at this Chicago hotel. Amenities include flat-screen TVs and WiFi. Stylish suites feature abundant space with comfortable seating and wet bar areas, creating an ideal setting for entertaining. On the Executive Level, enjoy private check-in, complimentary continental breakfast, hot and cold beverages, and an honor bar with evening appetizers.
This Chicago hotel features 130,000 sq. ft. of function space with over 77 meeting rooms, seven ballrooms and two exhibition halls. Lockwood Restaurant and Bar, located just off the lobby, is open throughout the day serving contemporary American cuisine. Small plates and classic cocktails are served in Potters Lounge. Balance Spa features 14 treatment rooms, including hydrotherapy services for the ultimate pampering. The fitness center offers over 10,000 sq. ft. of cardio and free weight equipment, an indoor pool, a whirlpool, and saunas.