This Program Project Grant application focuses on hemopoietic stem cell gene therapy with emphasis on stem cell gene therapy for the beta-chain hemoglobinopathies. The program addresses two aspects of Gene Therapy: globin gene therapy of patients with severe beta-thalassemia (thalassemia major or Cooley's anemia) using currently available lentiviral vector technologies;and the development of tools and approaches that will have an impact on gene therapy of the future. The program consists of four Projects and three Core Units. The objective of Project 1 is to identify all the potential chromatin insulators of the human genome, validate their insulator function, and develop new potent chromatin insulators for use in gene therapy vectors. The goal of Project 2 is to advance gene therapy of thalassemia by the approach of gene correction using iPS cells produced from mesenchymal cells or CD34 cells of patients with betathalassemia major. Project 3 addresses the question of bone marrow conditioning that is required for engraftment of corrected stem cells and proposes studies in animal models (mice and primates) that will result in the development of novel, less toxic bone marrow conditioning. Project 4 proposes a stem cell gene therapy clinical trial in patients with beta-thalassemia major. The trial will take place in two sites (New York and Thessaloniki, Greece) and will address the questions of safety and efficacy of stem cell mobilization and of bone marrow conditioning regimens in addition to the question of safety and efficacy of lentiviral globin gene transfer. Three core units support the projects. Core Unit A is the Administrative/ Clinical Regulatory core unit. Core Unit B is the Gene Therapy unit which will assist in the implementation of the clinical trial Core Unit C is the Genomics unit which will provide high throughput genomic services including vector integration site analysis for the patients to be treated with the lentiviral globin vectors. It is expected that the combined talent and expertise of the investigators of the basic sciences projects will lead to breakthroughs that will have an impact on the development of future gene therapy. It is also expected that the proposed clinical trials will answer the question of safety and efficacy of globin gene therapy in patients with betathalassemia major. Beta thalassemia and sickle cell disease are. among the most common genetic diseases in the world affecting several hundred thousand individuals. Although palliative treatments are available the only curative therapy is transplantation of bone marrow, but this therapy is available only to the minority of patients who have a compatible bone marrow donor. 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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Qasba, Pankaj
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Deyle, David R; Hansen, R Scott; Cornea, Anda M et al. (2014) A genome-wide map of adeno-associated virus-mediated human gene targeting. Nat Struct Mol Biol 21:969-75
Wurm, Melanie; Kowalski, John; Heckl, Dirk et al. (2014) Ectopic expression of HOXC6 blocks myeloid differentiation and predisposes to malignant transformation. Exp Hematol 42:114-25.e4
Boulad, Farid; Wang, Xiuyan; Qu, Jinrong et al. (2014) Safe mobilization of CD34+ cells in adults with ?-thalassemia and validation of effective globin gene transfer for clinical investigation. Blood 123:1483-6
Watts, Korashon L; Beard, Brian C; Wood, Brent L et al. (2014) No evidence of clonal dominance after transplant of HOXB4-expanded cord blood cells in a nonhuman primate model. Exp Hematol 42:497-504
Deyle, David R; Li, Li B; Ren, Gaoying et al. (2014) The effects of polymorphisms on human gene targeting. Nucleic Acids Res 42:3119-24
Chang, Kai-Hsin; Huang, Andy; Han, Hemei et al. (2013) Transcriptional environment and chromatin architecture interplay dictates globin expression patterns of heterospecific hybrids derived from undifferentiated human embryonic stem cells or from their erythroid progeny. Exp Hematol 41:967-979.e6
van Rensburg, R; Beyer, I; Yao, X-Y et al. (2013) Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells. Gene Ther 20:201-14
Yannaki, Evangelia; Karponi, Garyfalia; Zervou, Fani et al. (2013) Hematopoietic stem cell mobilization for gene therapy: superior mobilization by the combination of granulocyte-colony stimulating factor plus plerixafor in patients with *-thalassemia major. Hum Gene Ther 24:852-60
Groth, Amy C; Liu, Mingdong; Wang, Hao et al. (2013) Identification and characterization of enhancer-blocking insulators to reduce retroviral vector genotoxicity. PLoS One 8:e76528
Deyle, D R; Khan, I F; Ren, G et al. (2013) Lack of genotoxicity due to foamy virus vector integration in human iPSCs. Gene Ther 20:868-73

Showing the most recent 10 out of 142 publications