; 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.
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.
|Aker, Amira M; Johns, Lauren; McElrath, Thomas F et al. (2018) Associations between maternal phenol and paraben urinary biomarkers and maternal hormones during pregnancy: A repeated measures study. Environ Int 113:341-349|
|Bellavia, Andrea; Cantonwine, David E; Meeker, John D et al. (2018) Pregnancy urinary bisphenol-A concentrations and glucose levels across BMI categories. Environ Int 113:35-41|
|Rocco, Sabrina A; Koneva, Lada; Middleton, Lauren Y M et al. (2018) Cadmium Exposure Inhibits Branching Morphogenesis and Causes Alterations Consistent With HIF-1? Inhibition in Human Primary Breast Organoids. Toxicol Sci 164:592-602|
|Neier, K; Cheatham, D; Bedrosian, L D et al. (2018) Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice. J Dev Orig Health Dis :1-12|
|Schulz, Amy J; Mentz, Graciela B; Sampson, Natalie et al. (2018) Independent and Joint Contributions of Fine Particulate Matter Exposure and Population Vulnerability to Mortality in the Detroit Metropolitan Area. Int J Environ Res Public Health 15:|
|McClintock, Shannon D; Colacino, Justin A; Attili, Durga et al. (2018) Calcium-Induced Differentiation of Human Colon Adenomas in Colonoid Culture: Calcium Alone versus Calcium with Additional Trace Elements. Cancer Prev Res (Phila) 11:413-428|
|Milando, Chad W; Batterman, Stuart A (2018) Sensitivity analysis of the near-road dispersion model RLINE - an evaluation at Detroit, Michigan. Atmos Environ (1994) 181:135-144|
|Kochmanski, Joseph; Goodrich, Jaclyn M; Peterson, Karen E et al. (2018) Neonatal bloodspot DNA methylation patterns are associated with childhood weight status in the Healthy Families Project. Pediatr Res :|
|Ashrap, Pahriya; Watkins, Deborah J; Calafat, Antonia M et al. (2018) Elevated concentrations of urinary triclocarban, phenol and paraben among pregnant women in Northern Puerto Rico: Predictors and trends. Environ Int 121:990-1002|
|Smith, Jennifer A; Kho, Minjung; Zhao, Wei et al. (2018) Genetic effects and gene-by-education interactions on episodic memory performance and decline in an aging population. Soc Sci Med :|
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