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Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors

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Item Type:Article
Title:Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5/35++ vectors
Creators Name:Li, C. and Wang, H. and Gil, S. and Germond, A. and Fountain, C. and Baldessari, A. and Kim, J. and Liu, Z. and Georgakopoulou, A. and Radtke, S. and Raskó, T. and Pande, A. and Chiang, C. and Chin, E. and Yannaki, E. and Izsvak, Z. and Papayannopoulou, T. and Kiem, H.P. and Lieber, A.
Abstract:We tested a new in vivo hematopoietic stem cell (HSC) transduction/selection approach in rhesus macaques using HSC-tropic, integrating, helper-dependent adenovirus vectors (HDAd5/35++) designed for expression of human γ−globin in red blood cells (RBCs) to treat hemoglobinopathies. We show that HDAd5/35++ vectors preferentially transduce HSCs in vivo after intravenous injection into G-CSF/AMD3100-mobilized animals, and that transduced cells return to the bone marrow and spleen. The approach was well tolerated and activation of proinflammatory cytokines that is usually associated with intravenous adenovirus vector injection, was successfully blunted by pre-treatment with dexamethasone in combination with IL-1 and IL-6 receptor blockers. Using our MGMT(P140K)-based in vivo selection approach, γ-globin(+) RBCs increased in all animals with levels up to 90%. After selection, the percentage of γ-globin(+) RBCs declined most likely due to an immune response against human transgene products. Our biodistribution data indicate that γ-globin(+) RBCs in the periphery were mostly derived from mobilized HSCs that homed to the spleen. Integration site analysis revealed a polyclonal pattern and no genotoxicity related to transgene integrations. This is the first proof-of-concept study in nonhuman primates that in vivo HSC gene therapy could be feasible in humans without the need for high-dose chemotherapy conditioning and HSC transplantation.
Keywords:In Vivo, Hematopoietic Stem Cells, Adenovirus Vector, Nonhuman Primates, Hemoglobinopathies, Gamma Globin, Animals, Rhesus Macaques, Macaca Mulatta
Source:Molecular Therapy - Methods and Clinical Development
Publisher:Cell Press
Page Range:127-141
Date:10 March 2022
Additional Information:Erratum in: Mol Ther Methods Clin Dev 24: 127-141.
Official Publication:http://doi.org/10.1016/j.omtm.2021.12.003
PubMed:View item in PubMed

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