Genomes and Genes
Development of iPS Cells for Treatment of Hemoglobinopathies
Principal Investigator: Yuet Wai Kan
Abstract: DESCRIPTION (provided by applicant): The proposed POI is a multi-institutional grant that will develop a stem cell based therapy for the treatment of sickle cell disease (SCD) and [unreadable]-thalassemia ([unreadable]-thal) as well as other hemoglobinopathies, using patient derived somatic cells and reprogramming them into induced pluripotent stem (IPS) cells that will have their mutations corrected and ultimately differentiated into hematopoietic stem cells (HSCs) to reconstitute the patient's hematopoietic system. Development of an effective cellular therapy for the treatment of hemoglobinopathies, the most common inherited diseases worldwide, would significantly improve the quality of life of individuals afflicted with SCD and B-thalassemia that are common among the peoples of Africa, the Mediterranean, the Middle East, and Asia as well as their descendents in the U.S. This proposal will test the hypothesis that an effective cellular and genetic therapy for these diseases can be achieved in the context of this PPG through the generation, modification, and the hematopoietic differentiation of patient derived iPS cells. This will be accomplished through the following Projects: Project 1 will involve the conversion of a patient's somatic cells into IPS cells using phiC31 Integrase-mediated, sequence-specific integration of a plasmid carrying 2A peptide linked Oct4, Sox2, Klf4, and cMyc reprogramming cDNAs or by using small activating double stranded RNA (saRNA) to transiently enhance the expression of these reprogramming genes. Project 2 will involve correction of the disease causing mutations in the somatic cells and the iPS cells by sequence specific modification using either classical homologous recombination (HR) or by oligo/polynucleotide-based small fragment homologous replacement (SFHR) in the presence or absence of targeted zinc finger nucleases (ZFNs) or other meganucleases. Project 3 will involve exposure of uncorrected and corrected iPS cells to conditions to direct hematopoietic differentiation to generate HSCs which have the capacity to engraft and reconstitute the hematopoietic system. In the course of this PPG, all Projects will develop xeno-free systems to optimize safety. The science in the Projects will be augmented by an administrative (Core A) and 2 scientific Cores: Core B: Cell and Molecular Biology, and Core C: Cell Transplantation and Analysis.
Funding Period: 2011-09-30 - 2016-07-31
more information: NIH RePORT
- A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor networkSeung Tae Lee
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA
Nucleic Acids Res 40:11339-51. 2012....
- Identification of an astrovirus commonly infecting laboratory mice in the US and JapanTerry Fei Fan Ng
Blood Systems Research Institute, San Francisco, California, United States of America
PLoS ONE 8:e66937. 2013..This study demonstrates the need for metagenomic screening of laboratory animals to identify adventitious infections that may affect experimental outcomes. ..
- Blood cell-derived induced pluripotent stem cells free of reprogramming factors generated by Sendai viral vectorsLin Ye
Department of Medicine and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA
Stem Cells Transl Med 2:558-66. 2013..Maintenance of the genomic integrity of iPSCs without integration of exogenous DNA should allow the development of therapeutic-grade stem cells for regenerative medicine...
- Production of factor VIII by human liver sinusoidal endothelial cells transplanted in immunodeficient uPA miceMarina E Fomin
Blood Systems Research Institute, San Francisco, California, United States of America Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America
PLoS ONE 8:e77255. 2013..Demonstration of human FVIII production by transplanted LSECs encourages further pursuit of LSEC transplantation as a cellular therapy for the treatment of hemophilia A. ..
- Nuclease-mediated double-strand break (DSB) enhancement of small fragment homologous recombination (SFHR) gene modification in human-induced pluripotent stem cells (hiPSCs)R Geoffrey Sargent
Department of Otolaryngology Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA
Methods Mol Biol 1114:279-90. 2014..Using an allele-specific PCR (AS-PCR)-based cyclic enrichment protocol, clonal populations of corrected CF-iPS cells were isolated and expanded. ..
- The adult livers of immunodeficient mice support human hematopoiesis: evidence for a hepatic mast cell population that develops early in human ontogenyMarcus O Muench
Blood Systems Research Institute, San Francisco, California, United States of America Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America Liver Center, University of California San Francisco, San Francisco, California, United States of America
PLoS ONE 9:e97312. 2014..Thus, offering a model system to study the interaction of diverse human liver cell types that regulate hematopoiesis and immune function in the liver...
- Novel Methods to Assess the Effects of Chemicals on Child DevelopmentSusan L Schantz; Fiscal Year: 2013..This Center's research will fill an important gap in our knowledge by investigating the effects of these chemicals, both alone and combination with a high fat diet on reproductive and neural development. ..
- Endothelial Cell Phenotypes in Health and DiseaseWilliam C Aird; Fiscal Year: 2013..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
- Pathobiology of the Enteric SystemJoseph H Szurszewski; Fiscal Year: 2013..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
- Integrative Metabolic Adaptations to Enviromental and Nutritional ChallengeMORRIS JAY BIRNBAUM; Fiscal Year: 2013..The projects are supported by three Cores that provide histochemical analysis, generation of genetically modified mice, and their metabolic phenotyping. ..
- VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINSRichard E Waugh; Fiscal Year: 2013..The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program. ..
- Thrombus Formation and Antithrombotic InterventionJohn H Griffin; Fiscal Year: 2013..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
- INSULIN RECEPTORS AND THE GLUCOSE TRANSPORT SYSTEMJERROLD MICHAEL OLEFSKY; Fiscal Year: 2013..These studies should lead to an improved understanding of the basic causes of Type 2 diabetes mellitus and hold the potential for new therapeutic modalities. ..
- Immune Cells in Atherosclerosis and Vascular DiseaseCatherine C Hedrick; Fiscal Year: 2013..Each project will utilize the Human Core to study immune cells from human subjects to establish functional links between candidate genes of interest and immune cell function in atherogenesis. ..
- Cardiac Fibrillation: Mechanisms and TherapyJames N Weiss; Fiscal Year: 2013..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
- DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESISStuart H Orkin; Fiscal Year: 2013..abstract_text> ..
- Program Project: Growth, Differentiation and Disease of UrotheliumTung Tien Sun; Fiscal Year: 2013..abstract_text> ..
- PPG - Gene Therapy for Cystic Fibrosis Lung DiseasePaul B McCray; Fiscal Year: 2013..The discoveries from this PPG will accelerate the development of gene-based medicine for patients who suffer from this devastating disease...
- The Virtual Physiological Rat ProjectDaniel A Beard; Fiscal Year: 2013..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
- Basic and Clinical Studies of Cystic FibrosisRaymond A Frizzell; Fiscal Year: 2013..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
- UNMC EPPLEY CANCER CENTER SUPPORT GRANTKenneth H Cowan; Fiscal Year: 2013....
- Role of Eosinophils in Airway Inflammation and RemodelingNizar N Jarjour; Fiscal Year: 2013..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..
- Inflammatory responses of vascular cellsPaul L Fox; Fiscal Year: 2013..abstract_text> ..
- HORMONAL REGULATION OF BLOOD PRESSUREMichal Laniado Schwartzman; Fiscal Year: 2013..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
- Digitalis-Induced Signaling by Cardiac Na+/K+-ATPaseAmir Askari; Fiscal Year: 2013..abstract_text> ..
- EARLY EVENTS IN ALZHEIMER PATHOGENESISSUE TILTON GRIFFIN; Fiscal Year: 2013..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
- DIABETES AND ENDOCRINOLOGY RESEARCH CENTERDomenico Accili; Fiscal Year: 2013....
- Expanding Excellence in Developmental Biology in OklahomaLinda F Thompson; Fiscal Year: 2013..abstract_text> ..
- Jules Stein Eye Institute Core Grant for Vision ResearchWayne L Hubbell; Fiscal Year: 2013..Support in the form of the Core grant is requested to maintain these Modules through instrument service contracts, and to provide necessary personnel support to assist and train users and provide routine maintenance. ..
- Functional Consequences of Impaired Autophagy in AgingANA M CUERVO; Fiscal Year: 2013..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
- CARDIOVASCULAR DYNAMICS AND THEIR CONTROLJohn E Hall; Fiscal Year: 2013..End of Abstract) ..
- The Center for Native and Pacific Health Disparities ResearchMARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
- Molecular and Cellular Basis for Digestive DiseasesRichard M Peek; Fiscal Year: 2013..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
- Neurohumoral control of veins in hypertensionGregory D Fink; Fiscal Year: 2013..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
- Rocky Mountain Regional Center of Excellence or Biodefense and Emerging InfectiouJohn T Belisle; Fiscal Year: 2013..abstract_text> ..
- Regulatory Mechanisms In Intestinal MotilityKenton M Sanders; Fiscal Year: 2013..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
- Mechanistic Pharmacology of Anti-Mitotics and Apoptosis RegulationTimothy J Mitchison; Fiscal Year: 2013..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
- Osteocyte Regulation of Bone/Muscle with Age Lynda F Bonewald; Fiscal Year: 2013..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
- Gene Networks controlling macrophage-adipocyte interactions in insulinChristopher K Glass; Fiscal Year: 2013..abstract_text> ..
- STEM CELL GENE THERAPY FOR HEMOGLOBINOPATHIESGeorge Stamatoyannopoulos; Fiscal Year: 2013..The focus of this Program Project, Gene Therapy, can provide a new paradigm for the treatment of these hemoglobinopathies as well as for other blood diseases. (End of Abstract) ..
- Metabolic effects of adipose lipogenesisTimothy E McGraw; Fiscal Year: 2013....
- Invertebrate Models of Fat StorageJonathan M Graff; Fiscal Year: 2013..In Aim III, we will characterize the role that this E3 ligase has in fat biology;knowledge that is key in order to develop the fundamental insights required to ultimately manipulate the Adp pathway for therapeutic ends. ..
- The Role of H6PDH and 11beta-HSD1 in Type 2 Diabetes and ObesityYanjun Liu; Fiscal Year: 2013..Blocking the effects of H6PDH on 112-HSD1 may represent a new strategy in the effective treatment of type 2 diabetes and obesity through reduction of tissue GC availability mediating insulin sensitivity and glucose homeostasis. ..
- PAHs: New Technologies and Emerging Health RisksDavid E Williams; Fiscal Year: 2013..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..