; 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 B-thalassemia (B-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.

Public Health Relevance

This Program Project will focus on the development of a therapy for sickle cell anemia and B-thalassemia the most common genetic diseases worldwide. It aims to devise new methods of treating these diseases by genetically correcting patient cells to generate stems cells for transplantation, thus avoiding rejection due to histo-incompatibility. Correcting these diseases would significantly improve the quality of life among afflicted individuals and decrease the social and economic burden that they impose on the healthcare system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Center Core Grants (P30)
Project #
5P30ES017885-03
Application #
8451551
Study Section
Environmental Health Sciences Review Committee (EHS)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$14,744
Indirect Cost
$7,240
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Batterman, Stuart (2017) Review and Extension of CO?-Based Methods to Determine Ventilation Rates with Application to School Classrooms. Int J Environ Res Public Health 14:
Choi, Yoon-Hyeong; Park, Sung Kyun (2017) Environmental Exposures to Lead, Mercury, and Cadmium and Hearing Loss in Adults and Adolescents: KNHANES 2010-2012. Environ Health Perspect 125:067003
Sánchez, Brisa N; Kim, Sehee; Sammel, Mary D (2017) Estimators for longitudinal latent exposure models: examining measurement model assumptions. Stat Med 36:2048-2066
Park, Sung Kyun (2017) Ambient Air Pollution and Type 2 Diabetes: Do the Metabolic Effects of Air Pollution Start Early in Life? Diabetes 66:1755-1757
Patton, Allison P; Milando, Chad; Durant, John L et al. (2017) Assessing the Suitability of Multiple Dispersion and Land Use Regression Models for Urban Traffic-Related Ultrafine Particles. Environ Sci Technol 51:384-392
Ogbomo, Adesuwa S; Gronlund, Carina J; O'Neill, Marie S et al. (2017) Vulnerability to extreme-heat-associated hospitalization in three counties in Michigan, USA, 2000-2009. Int J Biometeorol 61:833-843
Yuan, Ye; Meeker, John D; Ferguson, Kelly K (2017) Serum polybrominated diphenyl ether (PBDE) concentrations in relation to biomarkers of oxidative stress and inflammation: The National Health and Nutrition Examination Survey 2003-2004. Sci Total Environ 575:400-405
Montrose, L; Faulk, C; Francis, J et al. (2017) Perinatal lead (Pb) exposure results in sex and tissue-dependent adult DNA methylation alterations in murine IAP transposons. Environ Mol Mutagen 58:540-550
Ferguson, Kelly K; Meeker, John D; McElrath, Thomas F et al. (2017) Repeated measures of inflammation and oxidative stress biomarkers in preeclamptic and normotensive pregnancies. Am J Obstet Gynecol 216:527.e1-527.e9
Price, Nathan D; Magis, Andrew T; Earls, John C et al. (2017) A wellness study of 108 individuals using personal, dense, dynamic data clouds. Nat Biotechnol 35:747-756

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