Genetically modified CD34+ cells as cellular vehicles for gene delivery into areas of angiogenesis in a rhesus model

Gómez-Navarro, Jesús; Contreras, Juan L.; Arafat, Waleed; Jiang, Xiaoyi; Krisky, David; Oligino, Thomas; Marconi, Peggy; Hubbard, Brandon T.; Glorioso, Joseph C.; Curiel, David T.; Thomas, Judith M.

doi:10.1038/sj.gt.3301054

Cited by 58 publications

(19 citation statements)

References 54 publications

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“…34 This study adds confirmatory evidence for the general potential utility of EPCs as a cellular vector. Gomez-Navarro and coworkers utilized a herpes vector to deliver the transgene whereas we utilized a retrovirus.…”

Section: Discussionsupporting

confidence: 55%

Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors

et al. 2003

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Human and mouse proliferation-competent, bone marrow or peripheral circulation derived endothelial progenitor-like cells (EPCs) were isolated, expanded and genetically engineered ex vivo to express the beta galactosidase (b-gal), green fluorescence protein or thymidine kinase (TK) genes using retrovirus-mediated gene transfer. Genetically labeled EPCs were transplanted into sublethally irradiated tumor-bearing mice and were found to migrate to and incorporate into the angiogenic vasculature of growing tumors while maintaining transgene expression. Ganciclovir treatment resulted in significant tumor necrosis in animals previously administered TK-expressing EPCs with no systemic toxicity. These results demonstrate the feasibility of using genetically modified EPCs as angiogenesis-selective gene-targeting vectors and the potential of this approach to mediate non-toxic and systemic antitumor responses.

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Section: Discussionsupporting

confidence: 55%

Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors

et al. 2003

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“…Recent evidence suggests that a component of the tumor-associated vasculature may be derived from the recruitment of circulating EPCs [19,26,27,28]. The VEGF produced in the homed circulating EPCs may augment angiogenesis and also exert a proliferative and antiapoptotic effect both on tumor and tumor ECs [29, 30].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hypoxia-Inducible Factor-1α and Endothelial Progenitor Cell Differentiation by Adenoviral Transfer of Small Interfering RNA in vitro

Jiang

Wang²,

Wang³

et al. 2006

J Vasc Res

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RNA interference is applied to study gene function in different organisms and in various cell types. Little is known about the effect of RNA interference on human endothelial progenitor cells (EPCs) in vitro. To address this issue, short hairpin RNA targeting the human hypoxia inducible factor-1α (HIF-1α) was transferred into human EPCs by an adenoviral vector. HIF-1α mRNA and protein expression was dramatically and specifically downregulated after adeno-small interfering RNA (siRNA)-HIF-1α infection in cells under hypoxia, a condition in which HIF-1α would have been induced. This effect persisted for at least 72 h and was accompanied by suppression of vascular endothelial growth factor (VEGF) mRNA and protein expression. The expression of endothelial cell markers CD31, VEGF receptor 2 (Flk-1) and eNOS as well as NO production were also markedly decreased. Functional studies showed HIF-1α knockdown via adenoviral siRNA transfer inhibited EPC colony formation, differentiation, proliferation and migration. These data indicate that specific gene knockdown via adenoviral transfer of siRNA is feasible in EPCs, and the effect is long-lasting. Our findings raise the possibility that such long-term modified human EPCs may be used to treat hypoxic tumor metastases that are known to be resistant to conventional therapeutic regimes.

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“…51 In addition the retroviral DNA randomly integrates into the host genome, posing a potential risk of oncogenesis. 52 Other viral vectors such as adenovirus, 25 lentivirus, 53 and herpes virus 54 have also been reported to transduce EPCs, but they have been used far less extensively than retroviral vectors.…”

Section: Isolation Characterization and Genetic Modification Of Epcsmentioning

confidence: 99%

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

et al. 2005

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Abstract-Endothelial dysfunction and cell loss are prominent features in cardiovascular disease. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. Several studies have shown the therapeutic potential of EPC transplantation in rescue of tissue ischemia and in repair of blood vessels and bioengineering of prosthetic grafts. Recent small-scale trials have provided preliminary evidence of feasibility, safety, and efficacy in patients with myocardial and critical limb ischemia. However, several studies have shown that age and cardiovascular disease risk factors reduce the availability of circulating EPCs (CEPCs) and impair their function to varying degrees. In addition, the relative scarcity of CEPCs limits the ability to expand these cells in sufficient numbers for some therapeutic applications. Priority must be given to the development of strategies to enhance the number and improve the function of CEPCs. Furthermore, alternative sources of EPC such as chord blood need to be explored. Strategies for improvement of cell adhesion, survival, and prevention of cell senescence are also essential to ensure therapeutic viability. Genetic engineering of EPCs may be a useful approach to developing these cells into efficient therapeutic tools. In the clinical arena there is pressing need to standardize the protocols for isolation, culture, and therapeutic application of EPC. Large-scale multi-center randomized trials are required to evaluate the long-term safety and efficacy of EPC therapy. Despite these hurdles, the outlook for EPC-based therapy for cardiovascular disease is promising. (Hypertension. 2005;46:7-18.)

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Genetically modified CD34+ cells as cellular vehicles for gene delivery into areas of angiogenesis in a rhesus model

Cited by 58 publications

References 54 publications

Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors

Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors

Inhibition of Hypoxia-Inducible Factor-1α and Endothelial Progenitor Cell Differentiation by Adenoviral Transfer of Small Interfering RNA in vitro

Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases

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