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In vivo hematopoietic stem cell gene therapy ameliorates murine thalassemia intermedia

Item Type:Article
Title:In vivo hematopoietic stem cell gene therapy ameliorates murine thalassemia intermedia
Creators Name:Wang, H. and Georgakopoulou, A. and Psatha, N. and Li, C. and Capsali, C. and Samal, H.B. and Anagnostopoulos, A. and Ehrhardt, A. and Izsvák, Z. and Papayannopoulou, T. and Yannaki, E. and Lieber, A.
Abstract:Current thalassemia gene therapy protocols require the collection of hematopoietic stem/progenitor cells (HSPCs), in vitro culture, lentivirus vector transduction, and retransplantation into myelo-ablated patients. Because of cost and technical complexity, it is unlikely that such protocols will be applicable in developing countries where the greatest demand for a beta-thalassemia therapy lies. We have developed a simple in vivo HSPC gene therapy approach that involved HSPC mobilization and an intravenous injection of integrating HDAd5/35++ vectors. Transduced HSPCs homed back to the bone marrow where they persisted long-term. HDAd5/35++ vectors for in vivo gene therapy of thalassemia had a unique capsid that targeted primitive HSPCs through human CD46, a relatively safe SB100X transposase-based integration machinery, a micro-LCR driven gamma-globin gene and, a MGMT(P140K) system that allowed for increasing the therapeutic effect by short-term treatment with low-dose O(6)BG/BCNU. We showed in "healthy" human CD46 transgenic mice and in a mouse model of thalassemia intermedia that our in vivo approach resulted in stable gamma-globin expression in the majority of circulating red blood cells. The high marking frequency was maintained in secondary recipients. In the thalassemia model, a near complete phenotypic correction was achieved. The treatment was well tolerated. This cost-efficient and "portable" approach could permit a broader clinical application of thalassemia gene therapy.
Keywords:Adenoviridae, Animal Disease Models, beta-Thalassemia, Cell Line, Erythrocytes, gamma-Globins, Gene Expression Regulation, Genetic Therapy, Genetic Transduction, Genetic Vectors, Hematopoietic Stem Cells, Transgenic Mice, Animals, Mice
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:598-615
Date:1 February 2019
Official Publication:https://doi.org/10.1172/JCI122836
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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