Development of a modified selective amplifier gene for hematopoietic stem cell gene therapy

Matsuda, Kyle; Kume, Akihiro; Ueda, Yasuji; Urabe, Masashi; Hasegawa, Mamoru; Ozawa, Keiya

doi:10.1038/sj.gt.3300906

Cited by 21 publications

(28 citation statements)

References 29 publications

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“…22 We previously developed a chimeric selective amplifier gene (SAG) composed of the signalling domain of the granulocyte colony-stimulating factor (G-CSF) receptor and the estrogen receptor hormone-binding domain, and demonstrated that primary bone marrow progenitor cells transduced with the SAG could be expanded in response to estrogen or tamoxifen in vitro. 18,23,24 The estrogen receptor-mediated dimerization of the chimeric gene product is assumed to be critical for the activation of the G-CSF receptor signaling. 25 We have further shown that in vivo expansion of transduced cells with the SAG is feasible in a murine transplantation model.…”

Section: Encoding the Sag And Reinfused Into Each Myeloablated Monkeymentioning

confidence: 99%

“…27 We previously demonstrated that this SAG (estrogen-responsive SAG, or designated GCRER) product predominantly transmits a proliferation signal by treatment with estrogen in vitro. 23 We constructed a further modified SAG in which a point mutation (G525R) was introduced into the estrogen receptor moiety of the GCRER (Figure 1). 24,28 This SAG product (tamoxifen-responsive SAG, or designated GCRTmR) no longer reacts to endogenous estrogen but reacts to synthetic hormones such as tamoxifen (Tm).…”

Section: Construct Of Retroviral Vectorsmentioning

confidence: 99%

“…23,24 The GCRER cDNA is a prototype SAG composed of two genes: (1) the murine G-CSF receptor (GCR) gene with deletion of the ligand-binding domain (amino acids 5-195 of the GCR) and with a point mutation (Y703F) to abolish the differentiation signal generated by the GCR; 27 and (2) the gene encoding the rat estrogen receptor (ER) hormone-binding domain (HBD). 23 The GCRTmR cDNA is a modified SAG. In the GCRTmR, a point mutation (G525R) was introduced into the ER gene moiety of the GCRER to abolish responsiveness to endogenous estrogen, but retain responsiveness to synthetic hormones such as tamoxifen (Tm).…”

Section: Vector Constructionmentioning

confidence: 99%

“…24,28 Four mouse stem cell virus (MSCV)-based vector plasmids expressing the enhanced green fluorescent protein (designated simply GFP in this article; Clontech, Palo Alto, CA, USA), expressing GCRER, expressing GCRTmR, and expressing both GCRER and GFP (GCRER/GFP) were constructed as described elsewhere (Figure 1). 23,24 These vector plasmids were transfected into the BOSC23 ecotropic packaging cell line by the calcium phosphate method as previously described. 46 Supernatants were harvested 48-60 h after transfection and were used to infect PG13 packaging cells using standard techniques 47 to generate retroviruses pseudotyped with the gibbon ape leukemia virus envelope.…”

Section: Vector Constructionmentioning

confidence: 99%

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

et al. 2002

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Section: Encoding the Sag And Reinfused Into Each Myeloablated Monkeymentioning

confidence: 99%

Section: Construct Of Retroviral Vectorsmentioning

confidence: 99%

Section: Vector Constructionmentioning

confidence: 99%

Section: Vector Constructionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2002

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“…18,19 Briefly, the murine phosphoglycerate kinase promoter-neomycin phosphotransferase cassette (EcoRI-SalI) in the murine stem cell virus (MSCV) 2.2 retrovirus vector (a generous gift of Dr. R. G. Hawley, University of Toronto, Toronto, Canada) was replaced with the murine CD8a cDNA under the control of the EMCV-derived IRES (nucleotides 259 -833 of EMCV-R genome) to construct MSCV/IRES-CD8a. The XhoI-BamHI fragment containing the ELS1 cDNA was obtained from pCR 2.1/ELS1 20 (kindly provided by the Pharmaceutical Research Laboratory, Kirin Brewery Co., Takasaki, Japan) and ligated into the multicloning sites of MSCV/IRESCD8a (the XhoI site and the BamHI site, respectively) to obtain the ELS1 IRES-CD8a cassette.…”

Section: Plasmid Constructionmentioning

confidence: 99%

A novel strategy for the tumor angiogenesis-targeted gene therapy: Generation of angiostatin from endogenous plasminogen by protease gene transfer

et al. 2000

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When NIH 3T3 fibroblasts were transduced with a retroviral vector containing a cDNA for porcine pancreatic elastase 1 and cultured in the presence of affinity-purified human plasminogen, the exogenously added plasminogen was digested to generate the kringle 1-3 segment known as angiostatin, a potent angiogenesis inhibitor. This was evidenced by immunoblot analysis of the plasminogen digests using a monoclonal antibody specifically reacting with the kringle 1-3 segment, and by efficient inhibition of proliferation of human umbilical vein endothelial cells by the plasminogen digests isolated from the culture medium of 3T3 fibroblasts. However, when Lewis lung carcinoma cells were transduced with the same vector and injected subcutaneously into mice in their back or via the tail vein, their growth at the injection sites or in the lungs was markedly suppressed compared with the growth of similarly treated nontransduced Lewis lung carcinoma cells. Nevertheless, the transduced cells were able to grow as avidly as the control cells in vitro. Assuming that the elastase 1 secreted from the transduced cells is likely to be exempt from rapid inhibition by its physiological inhibitor, ␣ 1 -protease inhibitor, as shown in the inflammatory tissues, the elastase 1 secreted from the tumor cells may effectively digest the plasminogen that is abundantly present in the extravascular spaces and generate the kringle 1-3 segment in the vicinity of implanted tumor cell clusters. Although the selection of more profitable virus vectors and cells to be transduced awaits further studies, such a protease gene transfer strategy may provide us with a new approach to anti-angiogenesis gene therapy for malignant tumors and their metastasis in vivo. Cancer Gene Therapy (2000) 7, 589 -596

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Inhibition of Sickle Hemoglobin Polymerization as a Basis for Therapeutic Approaches to Sickle‐Cell Anemia

Noguchi

Schechter

Haley³

et al. 2003

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews current understanding of the molecular and cellular basis of the pathophysiology of sickle‐cell anemia, with emphasis on the biophysics of the intracellular polymerization of sickle hemogobin. Factors that modify the severity of the disease manifestations, primarily by altering polymerization tendency, are discussed. This framework is used to present an overview of the major rational approaches to the therapy of sickle‐cell anemia based on inhibiting polymerization with agents that affect either the hemoglobin molecule or the sickle erythrocyte. Discussion of agents that may decrease vascular entrapment of sickle erythrocytes is also presented. Detailed review of the most important current approaches to therapy—pharmacologically elevating fetal hemoglobin—focuses primarily on hydroxyurea, the only drug currently FDA approved for treating sickle‐cell anemia. A brief discussion of other approaches, including stem cell transplantation and gene therapy, concludes the chapter.

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Development of a modified selective amplifier gene for hematopoietic stem cell gene therapy

Cited by 21 publications

References 29 publications

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

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

A novel strategy for the tumor angiogenesis-targeted gene therapy: Generation of angiostatin from endogenous plasminogen by protease gene transfer

Inhibition of Sickle Hemoglobin Polymerization as a Basis for Therapeutic Approaches to Sickle‐Cell Anemia

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