In vivo selective expansion of gene-modified hematopoietic cells in a nonhuman primate model

Hanazono, Yutaka; Nagashima, Takahiro; Takatoku, Masaaki; Shibata, Hiroaki; Ageyama, Naohide; Asano, Takayuki; Ueda, Yasuji; Dunbar, Cynthia E.; Kume, Akihiro; Terao, Keiji; Hasegawa, Mamoru; Ozawa, Keiya

doi:10.1038/sj.gt.3301781

Cited by 34 publications

(20 citation statements)

References 50 publications

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“…24,25 In the present study, we showed that functionally corrected cells were expandable using the SAG system in an actual disease model of CGD. An in vitro NBT assay showed that estrogen specifically induced functionally corrected colonies.…”

Section: Discussionmentioning

confidence: 95%

“…24,25 Blau and colleagues have presented another conditional expansion system in which an FK506-binding protein 12-based fusion receptor is activated by a dimerizing crosslinker, and no cancerous event has been reported. 19,40,41 Still more extensive studies are required to clear safety issues concerning uncontrolled proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…We showed that transduced hematopoietic stem/progenitor cells were expandable with this system in murine and primate models. 24,25 In the present study, a bicistronic retroviral vector carrying the human gp91 phox (hgp91) gene and a modified SAG was evaluated in a mouse model of X-CGD.…”

Section: Introductionmentioning

confidence: 99%

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Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene

et al. 2004

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Hematopoietic stem cell gene therapy has not provided clinical success in disorders such as chronic granulomatous disease (CGD), where genetically corrected cells do not show a selective advantage in vivo. To facilitate selective expansion of transduced cells, we have developed a fusion receptor system that confers drug-induced proliferation. Here, a 'selective amplifier gene (SAG)' encodes a chimeric receptor (GcRER) that generates a mitotic signal in response to estrogen. We evaluated the in vivo efficacy of SAGmediated cell expansion in a mouse disease model of X-linked CGD (X-CGD) that is deficient in the NADPH oxidase gp91 phox subunit. Bone marrow cells from X-CGD mice were transduced with a bicistronic retrovirus encoding GcRER and gp91 phox , and transplanted to lethally irradiated X-CGD recipients. Estrogen was administered to a cohort of the transplants, and neutrophil superoxide production was monitored. A significant increase in oxidase-positive cells was observed in the estrogen-treated mice, and repeated estrogen administration maintained the elevation of transduced cells for 20 weeks. In addition, oxidase-positive neutrophils were increased in the X-CGD transplants given the first estrogen even at 9 months post-transplantation. These results showed that the SAG system would enhance the therapeutic effects by boosting genetically modified, functionally corrected cells in vivo.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene

et al. 2004

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“…Macaque monkeys are widely used for preclinical testing of genes and proteins of human origin, taking advantage of their close phylogenetic relationship to humans [5,11,21]. Despite the genetic similarity between the two species, human gene products or proteins are often immunogenic to monkeys.…”

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confidence: 99%

Prevention of Immune Responses to Human Erythropoietin in Cynomologus Monkeys (Macaca fascicularis)

Ageyama

Hanazono

Shibata

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. Genes and proteins of human origin are often administered to monkeys for research purposes, however, it can be difficult to obtain sufficient levels of the products in vivo due to immunological clearance. In this study, we showed that human erythropoietin (hEPO) induces generation of anti-hEPO antibody in cynomolgus macaques (n=2), although 92% of amino acid residues are common between the human and macaque EPO. The administered hEPO was thus eliminated from the animals. On the other hand, when an immunosuppressant, cyclosporin A (CyA), was administered (6 mg/kg) intramuscularly every other day in combination with hEPO (n=2), no anti-hEPO antibody was generated and high serum levels of hEPO were obtained during administration of hEPO, resulting in an increase in serum hemoglobin levels. No adverse effects associated with CyA were observed. Thus, CyA treatment is useful for prevention of immune responses associated with the administration of human proteins in monkeys.

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“…New vectors and improvements in vector design, that is, lentivirus, foamy virus, and in vitro-packaged SV40 vectors, [27][28][29][30][31][32][33][34][35][36][37] and envelope proteins, 10,27,38-47 use of the CH-296 domain of fibronectin in transduction, [48][49][50][51][52][53][54][55][56] improved cytokine combinations, 52,[56][57][58][59] and changes in transduction methodology, that is, spinoculation and vector preloading, 43,51,56,[59][60][61][62][63][64][65] have improved gene transfer efficiency. 66,67 Improvement in gene transfer technology and the survival advantage of transduced HSCs resulted in the success of HSC gene therapy in patients with X-linked severe combined immune deficiency (X-SCID). However, retrovirus integration in three X-SCID patients was associated with the development of T-cell acute lymphoblastic leukemia (T-ALL).…”

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confidence: 99%

Hematopoietic stem cell gene therapy with drug resistance genes: an update

2005

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Transfer of drug resistance genes into hematopoietic stem cells (HSCs) has promise for the treatment of a variety of inherited, that is, X-linked severe combined immune deficiency, adenosine deaminase deficiency, thalassemia, and acquired disorders, that is, breast cancer, lymphomas, brain tumors, and testicular cancer. Drug resistance genes are transferred into HSCs either for providing myeloprotection against chemotherapy-induced myelosuppression or for selecting HSCs that are concomitantly transduced with another gene for correction of an inherited disorder. In this review, we describe ongoing experimental approaches, observations from clinical trials, and safety concerns related to the drug resistance gene transfer.

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In vivo selective expansion of gene-modified hematopoietic cells in a nonhuman primate model

Cited by 34 publications

References 50 publications

Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene

Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene

Prevention of Immune Responses to Human Erythropoietin in Cynomologus Monkeys (Macaca fascicularis)

Hematopoietic stem cell gene therapy with drug resistance genes: an update

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