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.
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