Transcriptional targeting of tumor endothelial cells for gene therapy

Dong, Zhihong

doi:10.1016/j.addr.2009.02.006

Cited by 30 publications

(25 citation statements)

References 142 publications

(157 reference statements)

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“…Both natural (vWF, FLT-1 and ICAM-2) and synthetic promoters have been used to drive endothelium-specific expression by viral and nonviral vectors. 91 The combination of highly specific promoters with highly efficient vectors (adenoviral, AAV and lentiviral) 92,93 will certainly improve initial outcomes in clinical trials of cardiovascular diseases.…”

Section: Endotheliummentioning

confidence: 99%

Physiological and tissue-specific vectors for treatment of inherited diseases

Toscano

Romero

Muñoz³

et al. 2010

Gene Ther

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After more than 1500 gene therapy clinical trials in the past two decades, the overall conclusion is that for gene therapy (GT) to be successful, the vector systems must still be improved in terms of delivery, expression and safety. The recent development of more efficient and stable vector systems has created great expectations for the future of GT. Impressive results were obtained in three primary immunodeficiencies and other inherited diseases such as congenital blindness, adrenoleukodystrophy or junctional epidermolysis bullosa. However, the development of leukemia in five children included in the GT clinical trials for X-linked severe combined immunodeficiency and the silencing of the therapeutic gene in the chronic granulomatous disease clearly showed the importance of improving safety and efficiency. In this review, we focus on the main strategies available to achieve physiological or tissue-specific expression of therapeutic transgenes and discuss the importance of controlling transgene expression to improve safety. We propose that tissue-specific and/or physiological viral vectors offer the best balance between efficiency and safety and will be the tools of choice for future clinical trials in GT of inherited diseases.

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Section: Endotheliummentioning

confidence: 99%

Physiological and tissue-specific vectors for treatment of inherited diseases

Toscano

Romero

Muñoz³

et al. 2010

Gene Ther

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“…Another obstacle is disease resistance emergence. Both of these challenges could be addressed by development of agents that would be systemically administered, home to the disease site, and express high levels of a therapeutic either persistently or under switchable control 2–6 .…”

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confidence: 99%

“…In oncology, the predominant goal has been vascular ablation. However, the strategy of “starving” tumors has elicited resistance either due to coordinate upregulation of untargeted factors by malignant cells, or dynamic micro environmental remodeling 2 . Other than hypervascular intraocular disease, vessel ablation would be contraindicated for most benign diseases.…”

mentioning

confidence: 99%

The myeloid-binding peptide adenoviral vector enables multi-organ vascular endothelial gene targeting

Kaliberov

Zhang

et al. 2014

Laboratory Investigation

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Vascular endothelial cells (ECs) are ideal gene therapy targets as they provide widespread tissue access and are the first contact surfaces following intravenous vector administration. Human recombinant adenovirus serotype 5 (Ad5) is the most frequently used gene transfer system because of its appreciable transgene payload capacity and lack of somatic mutation risk. However, standard Ad5 vectors predominantly transduce liver but not the vasculature following intravenous administration. We recently developed an Ad5 vector with a myeloid cell-binding peptide (MBP) incorporated into the knob-deleted, T4 fibritin chimeric fiber (Ad.MBP)1.This vector was shown to transduce pulmonary ECs presumably via a vector handoff mechanism. Here we tested the body wide tropism of the Ad.MBP vector, its myeloid cell necessity, and vector-EC expression dose response. Using comprehensive multi-organ co-immunofluorescence analysis, we discovered that Ad.MBP produced widespread EC transduction in lung, heart, kidney, skeletal muscle, pancreas, small bowel, and brain. Surprisingly, Ad.MBP retained hepatocyte tropism albeit at a reduced frequency compared with standard Ad5. While binding specifically to myeloid cells ex vivo, multi-organ Ad.MBP expression was not dependent on circulating monocytes or macrophages. Ad.MBP dose de-escalation maintained full lung targeting capacity but drastically reduced transgene expression in other organs. Swapping the EC-specific ROBO4 for the CMV promoter/enhancer abrogated hepatocyte expression but also reduced gene expression in other organs. Collectively, our multilevel targeting strategy could enable therapeutic biologic production in previously inaccessible organs that initiate the most debilitating or lethal human diseases.

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“…The rationale for transcriptional targeting of tumor endothelium is based on advances in the understanding of the molecular biology of angiogenesis (10). Thus, recent exploration of gene expression patterns has shown that tumor-associated endothelial cells are molecularly distinct from physiologic endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors

Brenner

Cohen

Breitbart

et al. 2013

Clinical Cancer Research

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Purpose: VB-111 is an antiangiogenic agent consisting of a nonreplicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a Fas-chimera transgene in angiogenic endothelial cells. In a phase I dose-escalation study, pharmacokinetics, pharmacodynamics, safety, and efficacy of a single dose of VB-111 in patients with advanced solid tumors were evaluated. Experimental Design: VB-111 was administered as a single i.v. infusion at escalating doses from 1 × 1010 (cohort 1) to 1 × 1013 (cohort 7) viral particles (VP) in successive cohorts. Assessments included pharmacokinetic and pharmacodynamic profiles, tumor response, and overall survival. Results: Thirty-three patients were enrolled. VB-111 was safe and well-tolerated; self-limited fever and chills were seen at doses above 3 × 1011 VPs. Transgene expression was not detected in blood but was detected in an aspirate from a subcutaneous metastasis after treatment. One patient with papillary thyroid carcinoma had a partial response. Conclusions: VB-111 was safe and well tolerated in patients with advanced metastatic cancer at a single administration of up to 1 × 1013 VPs. Evidence of transgene expression in tumor tissue and tumor response was observed. Clin Cancer Res; 19(14); 3996–4007. ©2013 AACR.

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Transcriptional targeting of tumor endothelial cells for gene therapy

Cited by 30 publications

References 142 publications

Physiological and tissue-specific vectors for treatment of inherited diseases

Physiological and tissue-specific vectors for treatment of inherited diseases

The myeloid-binding peptide adenoviral vector enables multi-organ vascular endothelial gene targeting

Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors

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