Abstract

We have developed a """"""""cell growth switch"""""""" that allows for the expansion of genetically modified primary hemopoietic cells both in vitro and in vivo. In particular, our f'mdings suggest that this approach may be especially well suited for the expansion of transduced erythroid cells. In view of the latent leukemias that emerged 3 years after gene therapy for X linked SCID, an extensive evaluation of the safety of this approach is warranted. The long-term safety and efficacy of CID administration will be evaluated in specific aim 1.
In specific aim 2 we will examine whether CIDs select for integrants adjacent to active genes, as well as potential toxicities associated with gene dosage.
In specific aims 3 - 5 we will examine whether the erythropoietin receptor is more favorable for the CID dependent selection of transduced erythroid cells than is mpl.
In specific aim 6 we will develop a vector designed to restrict expression of the growth switch to the erythroid lineage. In this manner we will examine both safety and efficacy while taking a deliberate course toward an eventual clinical trial of CID-regulating cell therapy for the inherited red cell disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL053750-14
Application #
7488344
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
14
Fiscal Year
2007
Total Cost
$300,365
Indirect Cost

  Institution

Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Constantinou, Varnavas C; Bouinta, Asimina; Karponi, Garyfalia et al. (2017) Poor stem cell harvest may not always be related to poor mobilization: lessons gained from a mobilization study in patients with ?-thalassemia major. Transfusion 57:1031-1039
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
Psatha, Nikoleta; Sgouramali, Eleni; Gkountis, Antonios et al. (2014) Superior long-term repopulating capacity of G-CSF+plerixafor-mobilized blood: implications for stem cell gene therapy by studies in the Hbb(th-3) mouse model. Hum Gene Ther Methods 25:317-27

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