Patient-Specific Induced Pluripotent Stem Cells for the Study of Neurological Diseases

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Patient-Specific Induced Pluripotent Stem Cells for the Study of Neurological Diseases

Friday, December 16, 2011

The New York Academy of Sciences

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Neurological disorders ranging from migraine and epilepsy to autism spectrum disorders, schizophrenia and Alzheimer's disease are affecting an increasingly larger percentage of the world’s population. Current treatments and therapies poorly manage symptoms and are rarely disease-modifying thus represent a significant unmet clinical need. Much of the difficulty in developing new treatments lies in the poor understanding of the underlying biology leading to these disorders. Induced pluripotent stem cells (iPSCs) are derived from adult somatic cells that, through genetic manipulation, have been reprogrammed to resemble embryonic pluripotent stem cells. Pluripotent stem cells have the unique property of unlimited proliferation in the undifferentiated state while retaining the ability to differentiate into terminal cell types, including neurons, when cultured appropriately. iPSCs from patients with neurological disorders offer the unprecedented opportunity to generate and study viable neurons that are potentially representative of the disease state. In this half day symposium, leaders in the field will discuss the generation of patient-specific iPSCs, their differentiation into neurons, and the search for disease-associated phenotypes. Investigators will highlight important issues regarding patient consent, choice of controls, and technical challenges, associated with this powerful technology that allows us to fill the gap between studies in humans and animals models in order to make breakthroughs for neurologic and psychiatric diseases.

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Agenda

* Presentation times are subject to change.


Friday December 16, 2011

1:00 PM

Opening Remarks
Jennifer Henry, PhD, The New York Academy of Sciences
Sandra Engle, PhD, Pfizer

1:15 PM

Modeling Peripheral Neuron Development, Disease and Therapy using Induced Pluripotent Stem Cells
Lorenz Studer, MD, Memorial Sloan-Kettering Cancer Center

1:55 PM

Novel Insights into the Neuronal Basis of Autism Spectrum Disorders using iPS Cells
Sergiu P. Pasca, MD, Stanford University School of Medicine

2:35 PM

Models of Chromosome 15q11-q13 Imprinting Disorders via Induced Pluripotent Stem Cell Technology Marc Lalande, PhD, University of Connecticut Health Center

3:15 PM

Coffee Break

3:40 PM

Patient Specific Induced Pluripotent Stem Cells for the Study of Neurological Diseases
Ole Isacson, MD, McLean Hospital and Harvard Medical School

4:20 PM

Modelling Psychiatric Disorders using Patient-Derived Induced Pluripotent Stem Cells
Hongjun Song, PhD, Johns Hopkins University

A 1-hour networking reception will follow the symposium.

Speakers

Organizers

Susan DeLaura

Cellular Dynamics International, Inc.

Susan DeLaura is responsible for the product management of human induced pluripotent stem cell-derived neurons and endothelial cells at Cellular Dynamics International, Inc (CDI). She brings more than 13 years of experience in the life science industry to CDI. Prior to joining CDI, she served as a Product Manager within EMD Chemicals for the Bioscience business unit. She was responsible strategic and tactical marketing and portfolio management of the Novagen brand flagship products. Additionally, she served as the Manager of Technical Services while at EMD. Susan's professional background also includes research in molecular and cell biology in the Department of Human Oncology at the University of Wisconsin-Madison, Comprehensive Cancer Center. While there, she studied the involvement of 4-aminobiphenol (4-ABP) and its derivatives in bladder cancer.

Sandra Engle, PhD

Pfizer

Sandra Engle is a Senior Principal Scientist in the Pluripotent Stem Cell Biology Laboratory of the Primary Pharmacology Group within Pfizer Inc. She received her Bachelor's of Art Degree in biology with an emphasis in human genetics from Ball State University in Muncie, Indiana. Sandra began her research career as an undergraduate studying Tcell response to cancer in the laboratory of Dr. M. Rita Young at the Indiana University Center for Medical Education. She obtained her PhD in Medical and Molecular Genetics from Indiana University School of Medicine in Indianapolis, Indiana, under the direction of Jay Tischfield for developing a knock-out mouse model of human APRT deficiency. She continued her interest in mouse models with post-doctoral fellowships at the University Of Cincinnati College Of Medicine in the laboratories of Dr. Nelson Horseman studying prolactin deficiency and signaling and Dr. Tom Doetschman studying transforming growth factor beta biology. Sandra moved to pharmaceutical research in 2001 with a position in the Genetically Engineered Mouse Models Group in Aventis (now Sanofi-Aventis) where she applied her skills to generating in vivo mouse knock-out models and in vitro mouse stem cell derived models. In 2004, she joined the Genetically Modified Models Research Center of Emphasis with Pfizer where she continued to generate in vivo and in vitro models. Currently, she leads the Pluripotent Stem Cell Biology Laboratory within Pfizer's Primary Pharmacology Group which focuses on the generation of human induced pluripotent stem cells, in vitro differentiation of stem cells to terminally differentiated cell types of interest and the genetic modification of human stem cells.

Mercedes Beyna, MS

Pfizer

Mercedes Beyna is currently a research scientist at Pfizer, where she is using molecular, cellular, genetic, and imaging approaches in the quest to understand the biology underlying autism spectrum disorders. Captivated by neuroscience, she has worked in the field for over 10 years, in both academic and industrial laboratory settings. Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from New York University. As an active member of the Biochemical Pharmacology Discussion Group, she enjoys developing interesting and educational symposia.

Ken Jones, PhD

Biochemical Pharmacology Discussion Group

Ken received his PhD in Physiology at Rutgers University studying neuronalnetworks that control behaviors of model organisms. During postdoctoral training at Harvard Medical School with Robert Baughman he developed mammalian primary cell culture techniques to map NMDA and AMPA receptors at synaptic and extrasynaptic sites. His subsequent research in biotech and pharmaceutical companies has provided a number of promising novel drug targets for psychiatric and neurological disorders. At Synaptic Pharmaceutical Corp he co-discovered the heterodimeric nature of GABAB receptors, a newphotoreceptor that regulates circadian rhythms, as well as several novel hypothalamic neuropeptide receptors. In his most recent position at Lundbeck Research (Paramus, NJ) he was responsible for capital and process improvements that dramatically improved assay throughput in the HTS group, and he served leadership roles in a handful of early to late-stage drug discovery projects. He has enjoyed co-organizing a variety of NYAS symposium under the auspices of the Biochemical Pharmacology Discussion Group.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Ole Isacson, MD

McLean Hospital and Harvard Medical School

Dr. Ole Isacson is Professor of Neurology (Neuroscience) at Harvard Medical School. He is the Director, Chair of the Neuroregeneration Research Institute at McLean Hospital. The Neuroregeneration Institute focuses on advancing conceptually novel therapies for Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic Lateral Sclerosis and related neurodegenerative or neuropsychiatric diseases. Its goal is to provide cutting edge research that can be translated into relevant therapeutic gains for patients in need. The Institute works with other research teams, governmental agencies, and pharmaceutical companies to maximize the therapeutic benefits of this research. Dr Isacson is also Principal Faculty of the Harvard Stem Cell Institute, and a member of the Scientific Advisory Boards for the Harvard NeuroDiscovery Center and the Michael J. Fox Foundation. He is the past Receiving Editor of the European Journal of Neuroscience, current Editor in Chief of Molecular and Cellular Neuroscience, and a member of many Editorial Boards. Dr Isacson has published over 280 original peer-reviewed scientific articles and reviews in his fields, and he, his laboratory and collaborators have received several awards for this work.

Marc Lalande, PhD

University of Connecticut Health Center

After receiving a PhD in Medical Biophysics from the University of Toronto, Marc Lalande pursued postdoctoral training in the Department of Pediatrics, Harvard Medical School and Children's Hospital, Boston, MA. He was Assistant Professor, Department of Pathology and Center for Human Genetics, McGill University, Montreal, Québec before returning to Boston Children's Hospital. He remained at Harvard Medical School as an Associate Professor of Pediatrics and an Assistant Investigator of the Howard Hughes Medical Institute until 1998. He is currently Physicians Health Services Professor and Chairman of the Department of Genetics Developmental Biology and Director of the University of Connecticut Stem Cell Institute. His area of expertise is human molecular genetics and genomic imprinting.

Sergiu P. Pasca, MD

Stanford University School of Medicine

Dr. Sergiu Pasca is a postdoctoral research fellow in the Department of Neurobiology at Stanford University. Sergiu has a long-standing interest in understanding mechanisms underlying neurodevelopmental disorders. During his medical studies in Romania he worked in the laboratory of Dr. Maria Dronca towards understanding metabolic disturbances in children with autism spectrum disorders. During this time, Sergiu also spent time training in neurophysiology of the visual cortex in Dr. Danko Nikolic's lab at the Max Planck Institute for Brain Research in Germany. In 2009, he joined the laboratory of Dr. Ricardo Dolmetsch at Stanford University, where he is using the induced pluripotent stem cell (iPSC) technology to identify cellular endophenotypes for neuropsychiatric diseases.

Hongjun Song

Johns Hopkins University

Hongjun Song, PhD is a Professor in the Departments of Neurology and Neuroscience, Director of the Stem Cell Biology Program in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. Dr. Song is a leader in the research of adult neural stem cells and neurogenesis. He has published many high profile papers from his laboratory, including in Nature, Science, and Cell, as well as many influential reviews in Annual Reviews of Neuroscience and Current Opinion in Neurobiology. Dr. Song has won several awards including the Klingenstein Fellowship Awards in the Neuroscience (2003), McKnight Scholar Award (2006), Inaugural Young Investigator Award of the Chinese Biological Investigators Society (2008), NARSAD Independent Investigator Award (2008), and the Rising Star Award from International Mental Health Research Organization (2009). He was honored in 2008 with Young Investigator Award from the Society for Neuroscience. He is a member of the Faculty of 1000 Biology Neurobiology of Disease and Regeneration Section of the Neuroscience Faculty and on the editorial board for several journals. Dr Song's has pioneered using the "single-cell genetics" approach to examine development of new neurons from neural stem cells in adult animals in combination with state-of-the-art technologies in confocal and electron microscopy, multiphoton confocal imaging, and electrophysiology. His laboratory also established the methodology to derive patient-specific induced pluripotent stem cells to model human neurological diseases, to understand disease mechanisms and to screen drugs.

Lorenz Studer, MD

Memorial Sloan-Kettering Cancer Center

A native of Switzerland, Lorenz Studer graduated from medical school in 1991 and received his doctoral degree in neuroscience at the University of Bern in 1994. While there, he initiated studies with Christian Spenger, MD, leading to the first clinical trial of fetal tissue transplantation for Parkinson's disease in Switzerland in December 1995. Studer next pursued his research interests at the National Institutes of Health (NIH) in Bethesda, Maryland, where he worked in the laboratory of Ronald D. McKay, PhD. At the NIH he pioneered techniques that allow the generation of dopamine cells in culture from dividing precursor cells. In 1998, he was first to demonstrate that the transplantation of dopamine cells generated in culture improve clinical symptoms in Parkinsonian rats.

In 2000, he moved to New York City where he started his own research program at the Memorial Sloan-Kettering Cancer Center with a focus on stem cells and brain repair. Major early contributions of his lab were the in vitro derivation of midbrain dopamine neurons from embryonic stem cells, mouse nuclear transfer embryonic stem cells and from a novel type of pluripotent parthenogenetic stem cell in monkey. His laboratory was also first to demonstrate "therapeutic cloning" in a mouse model of a CNS disorder, and he has pioneered studies on the directed differentiation, high-throughput screening and genetic modification of human ES cells. His most recent work increasingly focuses on the biology of human ES cells and human induced pluripotent stem cells developing novel strategies at the interface of developmental biology, regenerative medicine and disease modeling.

Studer is the founding director of the Sloan-Kettering Center for Stem Cell Biology a Member in the Developmental Biology Program and the Department of Neurosurgery and Professor in Neuroscience at Weill-Cornell Graduate School. He also currently heads the steering committee of the Tri-institutional stem cell initiative (Sloan-Kettering Institute, Weill-Cornell Medical School, and Rockefeller University).

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Abstracts

Patient Specific Induced Pluripotent Stem Cells as Models of Neurological Disease and use in Regenerative Medicine
Ole Isacson, MD, McLean Hospital and Harvard Medical School

To understand the biology and any convergence of risk factors that lead to dysfunction in specific neural cell populations, we have created induced pluripotent stem cells (iPS) from fibroblasts of patients with several key genetic forms of Parkinson’s disease or no disease. We are determining cell type specific vulnerabilities in the CNS using diverse populations of neural cells, or purified populations of neurons. Our preliminary data from such gPDiPS-derived neural cells indicate that mitochondrion-associated disease phenotypes can be determined using in vitro toxicity assays.
 
Human neurons mature too slowly for extensive functional studies in vitro. Since elaborate patterns of axonal arborization and connections cannot be established in vitro, we use complementary in vivo rodent transplantation bioassays, including physiology, to test hypotheses in implanted gPDiPS or genetically rescued iPS-derived neurons. The most important objective is translation of the cellular data and assays into prototype discovery tools.
 
We have begun to examine how several genetic intracellular pathways can interact to create cellular dysfunction in combination with environmental stressors (non-autonomous), as well as validating human PDiPS cells in vitro and in vivo models for more in depth mechanistic studies and discovery. These assays are a first step for human cell assays for individualized screens for new PD therapeutics.

Models of Chromosome 15q11-q13 Imprinting Disorders via Induced Pluripotent Stem Cell Technology
Marc Lalande, PhD, University of Connecticut Health Center

We are studying three imprinting disorders: the Prader-Willi (PWS), Angelman (AS) and 15q11-q13 duplication (Dup15q) syndromes. Clinical features include hyperphagia/obesity and behavioral problems in PWS; ataxia, microcephaly, epilepsy and severe intellectual disability in AS; and autism, motor delay and macrocephaly in Dup15q. Chromosome 15q11-13 is subject to genomic imprinting and deletion of the paternal copy of this region causes PWS while loss of the maternal copy causes AS. Dup15q syndrome results from duplication of maternally-inherited chromosome 15q11-13. We have generated iPSCs and derived neurons from patients with all three syndromes as well as control individuals. In the case of PWS, we are testing the hypothesis that deletion of the paternal chromosome 15q11-q13 leads to abnormal expression of genes outside this chromosomal region through the use of next-generation sequencing (RNA-seq) of iPSC-derived neurons. We are validating the PWS-specific transcriptional changes by qRT-PCR in iPSC-derived neurons as well as in patient and normal brain samples. In the case of AS, we are studying the mechanism of silencing of the paternal allele of the Angelman disease gene, ubiquitin protein ligase E3A (UBE3A). In the case of Dup15q syndrome, we are testing the hypothesis that the increase in UBE3A copy number resulting from maternal duplication contributes to the disease mechanism. We believe that these studies will lead to a better understanding the chromosome 15q imprinting disorders and set the stage for the development of therapeutic strategies.

Novel insights into the Neuronal basis of Autism Spectrum Disorders using iPS Cells
Sergiu P. Pasca, MD, Stanford University School of Medicine

The successful reprogramming of human somatic cells into induced pluripotent stem cells (iPSC) and their subsequent in vitro differentiation into various cell types can serve as a powerful platform for human disease modeling. Dysfunction of L-type voltage gated calcium channels (LTCCs) has been implicated in the pathophysiology of mood disorders, schizophrenia and autism spectrum disorders. We utilized iPSC technology to investigate the pathogenesis of Timothy syndrome, a monogenic form of autism caused by a point mutation in the LTCC Cav1.2. Patient neural progenitor cells and neurons showed defects in calcium (Ca2+) signaling and activity-dependent gene expression. In addition, Timothy syndrome patient-derived cultures exhibited changes in the distribution of specific subpopulations of neurons and dendritic abnormalities. These results suggest that iPSC-derived neurons are a promising approach for studying the underlying cellular defects that lead to psychiatric disorders.

Modelling Psychiatric Disorders using Patient-derived Induced Pluripotent Stem Cells
Hongjun Song, Johns Hopkins University

Substantial evidence suggests schizophrenia and related mental disorders is developmental in nature and has significant genetic contribution. Recent advances in stem cells biology leads to technologies to reprogram somatic cells from patients into pluripotent stem cells, named iPSCs. Such technology offers possibilities to study development of human neurons from patients with defined mutations. Disrupted-in-schizophrenia 1 (DISC1) is a prominent risk gene for schizophrenia and other major mental disorders. We have generated iPSCs from several family members with specific mutation in the DISC1 gene. I will present latest findings of our studies of neuronal development of iPSCs derived from this family.   

Modeling Peripheral Neuron Development, Disease and Therapy using Induced Pluripotent Stem Cells
Lorenz Studer, MD, Memorial Sloan-Kettering Cancer Center

Human iPSCs represent a powerful and potentially unlimited source to generate disease-relevant cell types for applications in regenerative medicine and disease modeling.  However, strategies to direct neural differentiation in human pluripotent cells have been hampered by the lack of defined culture conditions, the slow and poorly synchronized pace of differentiation, variable outcome and high cost. We have recently demonstrated efficient neural conversion of human pluripotent cells by dual inhibition of SMAD signaling. Here we present data on a second generation of SMAD inhibition protocols. These new protocols are based on the combinatorial use of small molecules to generate a broad range of neural cell types at unprecedented speed and efficiency and at minimal cost.

One key application for iPSC derived neural cell types is the modeling of human genetic disease. We have recently demonstrated modeling of Familial Dysautonomia in patient specific iPSCs. Here we will highlight the current status of using FD-iPSC disease modeling and its application in validating candidate therapies as well as in primary and drug discovery. We will also discuss progress on modeling other neural crest related disorders and address some of the current challenges of these approaches.

 

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