Recombinant Self-Complementary Adeno-Associated Virus Serotype Vector-Mediated Hematopoietic Stem Cell Transduction and Lineage-Restricted, Long-Term Transgene Expression in a Murine Serial Bone Marrow Transplantation Model
| Autor: | Daniela Bischof, Njeri Maina, Kirsten A. Weigel-Van Aken, Li Zhong, Zongchao Han, Zhongbo Hu, Arun Srivastava, Xiaomiao Li, Mervin C. Yoder, William B. Slayton |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Time Factors Genetic enhancement Genetic Vectors DNA Recombinant Gene Expression Biology medicine.disease_cause Mice Transduction (genetics) Transduction Genetic Genetics medicine Animals Cell Lineage Transgenes Molecular Biology Adeno-associated virus Bone Marrow Transplantation Blood Cells Hematopoietic stem cell Dependovirus Hematopoietic Stem Cells Virology Mice Inbred C57BL Transplantation Haematopoiesis medicine.anatomical_structure Models Animal Molecular Medicine Female Bone marrow Stem cell Genetic Engineering |
| Zdroj: | Human Gene Therapy. 19:376-383 |
| ISSN: | 1557-7422 1043-0342 |
| Popis: | Although conventional recombinant single-stranded adeno-associated virus serotype 2 (ssAAV2) vectors have been shown to efficiently transduce numerous cells and tissues such as brain and muscle, their ability to transduce primary hematopoietic stem cells (HSCs) has been reported to be controversial. We have previously documented that among the ssAAV serotype 1 through 5 vectors, ssAAV1 vectors are more efficient in transducing primary murine HSCs, but that viral second-strand DNA synthesis continues to be a rate-limiting step. In the present studies, we evaluated the transduction efficiency of several novel serotype vectors (AAV1, AAV7, AAV8, and AAV10) and documented efficient transduction of HSCs in a murine serial bone marrow transplantation model. Self-complementary AAV (scAAV) vectors were found to be more efficient than ssAAV vectors, and the use of hematopoietic cell-specific enhancers/promoters, such as the human beta-globin gene DNase I-hypersensitive site 2 enhancer and promoter (HS2-betap) from the beta-globin locus control region (LCR), and the human parvovirus B19 promoter at map unit 6 (B19p6), allowed sustained transgene expression in an erythroid lineage-restricted manner in both primary and secondary transplant recipient mice. The proviral AAV genomes were stably integrated into progenitor cell chromosomal DNA, and did not lead to any overt hematological abnormalities in mice. These studies demonstrate the feasibility of the use of novel scAAV vectors for achieving high-efficiency transduction of HSCs as well as erythroid lineage-restricted expression of a therapeutic gene for the potential gene therapy of beta-thalassemia and sickle cell disease. |
| Databáze: | OpenAIRE |
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