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

Njeri Maina, Zongchao Han, Xiaomiao Li, Zhongbo Hu, Li Zhong, Daniela Bischof, Kirsten A. Weigel-Van Aken, William B. Slayton, Mervin Yoder, Arun Srivastava

Research output: Contribution to journalArticle

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Abstract

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 β-globin gene DNase I-hypersensitive site 2 enhancer and promoter (HS2-βp) from the β-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 β-thalassemia and sickle cell disease.

Original languageEnglish
Pages (from-to)376-383
Number of pages8
JournalHuman Gene Therapy
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2008

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Dependovirus
Cell Lineage
Hematopoietic Stem Cells
Bone Marrow Transplantation
Transgenes
Globins
Locus Control Region
Human Parvovirus B19
Thalassemia
Deoxyribonuclease I
DNA
Sickle Cell Anemia
Feasibility Studies
Genetic Therapy
Genes
Stem Cells
Genome
Muscles
Serogroup
Brain

ASJC Scopus subject areas

  • Genetics

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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. / Maina, Njeri; Han, Zongchao; Li, Xiaomiao; Hu, Zhongbo; Zhong, Li; Bischof, Daniela; Weigel-Van Aken, Kirsten A.; Slayton, William B.; Yoder, Mervin; Srivastava, Arun.

In: Human Gene Therapy, Vol. 19, No. 4, 01.04.2008, p. 376-383.

Research output: Contribution to journalArticle

Maina, Njeri ; Han, Zongchao ; Li, Xiaomiao ; Hu, Zhongbo ; Zhong, Li ; Bischof, Daniela ; Weigel-Van Aken, Kirsten A. ; Slayton, William B. ; Yoder, Mervin ; Srivastava, Arun. / 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. In: Human Gene Therapy. 2008 ; Vol. 19, No. 4. pp. 376-383.
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