The goal os this program project is to develop approaches for gene therapy for the beta-chain hemoglobinopathies: sickle cell anemia and homozygous beta-thalassemia. The program consists of five projects and four core units. The objective of this project is to develop vectors that will result in the production of therapeutic levels of fetal hemoglobin in the red cell progeny of transduced stem cells. The next projects focus on the development of new vector technologies for stem cell gene therapy: foamy viral vectors and deleted adeno AAV vectors. Success in the development of these new vectors will have a major impact on the field of stem cell gene therapy. The next project uses a new technology, based on chemical inducers of dimerization to achieve in vivo selection of genetically modifier stem cells. The final project studies oncoretroviral and lentiviral vectors in the baboon model and attempts new approaches for improving stem cell transduction. Unit A is a SCID/NOD mice unit and will assist investigators in the assessment of gene transfer into human stem cells. Unit B will assist the projects with cell biology and globin expression studies. Unit C will perform bone marrow transplantation in baboons to assess gene transfer into the stem cells of primates. Unit D will provide administrative support.
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| Gori, Jennifer L; Butler, Jason M; Kunar, Balvir et al. (2017) Endothelial Cells Promote Expansion of Long-Term Engrafting Marrow Hematopoietic Stem and Progenitor Cells in Primates. Stem Cells Transl Med 6:864-876 |
| Psatha, Nikoletta; Karponi, Garyfalia; Yannaki, Evangelia (2016) Optimizing autologous cell grafts to improve stem cell gene therapy. Exp Hematol 44:528-39 |
| Li, Li B; Ma, Chao; Awong, Geneve et al. (2016) Silent IL2RG Gene Editing in Human Pluripotent Stem Cells. Mol Ther 24:582-91 |
| Karponi, Garyfalia; Psatha, Nikoletta; Lederer, Carsten Werner et al. (2015) Plerixafor+G-CSF-mobilized CD34+ cells represent an optimal graft source for thalassemia gene therapy. Blood 126:616-9 |
| Vierstra, Jeff; Reik, Andreas; Chang, Kai-Hsin et al. (2015) Functional footprinting of regulatory DNA. Nat Methods 12:927-30 |
| Qi, Heyuan; Liu, Mingdong; Emery, David W et al. (2015) Functional validation of a constitutive autonomous silencer element. PLoS One 10:e0124588 |
| Liu, Mingdong; Maurano, Matthew T; Wang, Hao et al. (2015) Genomic discovery of potent chromatin insulators for human gene therapy. Nat Biotechnol 33:198-203 |
| Polak, Paz; Karli?, Rosa; Koren, Amnon et al. (2015) Cell-of-origin chromatin organization shapes the mutational landscape of cancer. Nature 518:360-364 |
| Chandrasekaran, Devikha; Nakamoto, Betty; Watts, Korashon L et al. (2014) Modeling promising nonmyeloablative conditioning regimens in nonhuman primates. Hum Gene Ther 25:1013-22 |
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