; 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.
|Watkins, Deborah J; Ferguson, Kelly K; Anzalota Del Toro, Liza V et al. (2015) Associations between urinary phenol and paraben concentrations and markers of oxidative stress and inflammation among pregnant women in Puerto Rico. Int J Hyg Environ Health 218:212-9|
|Schulz, Amy J; Mentz, Graciela B; Sampson, Natalie R et al. (2015) Effects of particulate matter and antioxidant dietary intake on blood pressure. Am J Public Health 105:1254-61|
|Ferguson, Kelly K; McElrath, Thomas F; Chen, Yin-Hsiu et al. (2015) Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth. Am J Obstet Gynecol 212:208.e1-8|
|Handal, Alexis J; McGough-Maduena, Alison; Páez, Maritza et al. (2015) A Pilot Study Comparing Observational and Questionnaire Surrogate Measures of Pesticide Exposure Among Residents Impacted by the Ecuadorian Flower Industry. Arch Environ Occup Health 70:232-40|
|Boldenow, Erica; Hogan, Kelly A; Chames, Mark C et al. (2015) Role of cytokine signaling in group B Streptococcus-stimulated expression of human beta defensin-2 in human extraplacental membranes. Am J Reprod Immunol 73:263-72|
|Nahar, Muna S; Liao, Chunyang; Kannan, Kurunthachalam et al. (2015) In utero bisphenol A concentration, metabolism, and global DNA methylation across matched placenta, kidney, and liver in the human fetus. Chemosphere 124:54-60|
|Meeker, John D; Ferguson, Kelly K (2014) Urinary phthalate metabolites are associated with decreased serum testosterone in men, women, and children from NHANES 2011-2012. J Clin Endocrinol Metab 99:4346-52|
|O'Brien, E; Bergin, I L; Dolinoy, D C et al. (2014) Perinatal bisphenol A exposure beginning before gestation enhances allergen sensitization, but not pulmonary inflammation, in adult mice. J Dev Orig Health Dis 5:121-31|
|Faulk, Christopher; Barks, Amanda; Sánchez, Brisa N et al. (2014) Perinatal lead (Pb) exposure results in sex-specific effects on food intake, fat, weight, and insulin response across the murine life-course. PLoS One 9:e104273|
|Park, Yongseok; Figueroa, Maria E; Rozek, Laura S et al. (2014) MethylSig: a whole genome DNA methylation analysis pipeline. Bioinformatics 30:2414-22|
Showing the most recent 10 out of 119 publications