Suppression of the immune response to an adenovirus vector and enhancement of intratumoral transgene expression by low-dose etoposide

Bouvet, Michael; Fang, Bingliang; Ekmekçioglu, Sühendan; Ji, Lin; Bucana, Corazon D.; Hamada, Katsuyuki; Grimm, Elizabeth A.; Roth, Jack A.

doi:10.1038/sj.gt.3300564

Cited by 65 publications

(32 citation statements)

References 14 publications

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“…1,3 Previous studies addressing repeated dosing with rAAV vectors have provided contradicting data. Successful repeated administration after pretreatment of the host with immunosuppressing antibodies, 19 and/or immunemodulating agents 20 or broad immunosuppressing agents, 21 has been reported. Independent of immunosuppressive/modulating regimens, two studies have observed that rAAV may be efficiently Figure 4 Development of NAB (a) and biodistribution (b) in female BALB/c mice after intratracheal and intranasal application of 10 10 and 10 9 AAV-luc (n¼5).…”

Section: Discussionmentioning

confidence: 99%

“…17,18 A number of studies have reported successful repeated administration after pretreatment of the host with immunosuppressing antibodies, 19 and/or immune-modulating agents 20 or broad immunosuppressing agents, such as cyclophosphamide. 21 In contrast to the use of immunosuppressive/modulating regimens, two studies have observed that rAAV may be efficiently administered a second time if the time between administrations is extended beyond approximately 28 weeks and the capsid is derived from AAV5 or AAV9. 8,22 These encouraging results are contradicted by Sumner-Jones et al, 17 where administration of rAAV5 resulted in the production of sustained anti-AAV5 capsid-NAB that substantially lowered lung gene transfer on a second administration and effectively abolished it on a third.…”

Section: Introductionmentioning

confidence: 99%

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Adeno-associated virus serotype 9-mediated pulmonary transgene expression: effect of mouse strain, animal gender and lung inflammation

et al. 2011

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Gene therapy holds great potential for the treatment of various acquired and inherited pulmonary diseases. Among various viral vectors, adeno-associated viral (AAV) vectors have been most frequently used in different clinical trials of pulmonary gene therapy. In the present study, we examined the kinetics and duration of transgene expression, vector biodistribution and development of neutralizing antibodies (NAB) in mice after pulmonary application of AAV2/9 vector. The pulmonary route of application did not affect any of the measured parameters. Transgene expression and biodistribution analysis at day 450 post-application confirmed the systemic spread of the vector after pulmonary delivery. Using SPB À/À mice, the study shows that AAV2/9-mediated gene expression is influenced by animal gender but not mouse genotype and is insensitive to the presence of lung inflammation. Lower expression levels were observed in male compared with female mice, and transient immunosuppression with dexamethasone significantly reduced the development of NAB in both genders of mice. The study thus advances this serotype for further development and use as a therapeutic vector.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adeno-associated virus serotype 9-mediated pulmonary transgene expression: effect of mouse strain, animal gender and lung inflammation

et al. 2011

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“…In human tumors, p63 is not frequently mutated like p53, but certain isoforms are occasionally lacked or overexpressed (Crook et al, 2000;Hibi et al, 2000;Nylander et al, 2000;Park et al, 2000;Senoo et al, 2001a). It is known that p53 represses VEGF expression (Bouvet et al, 1998;Fontanini et al, 1998;Mukhopadhyay et al, 1995), which is considered to be a critical regulator for tumor growth. In this study, we have investigated functional roles of p63 on VEGF expression.…”

Section: Discussionmentioning

confidence: 99%

“…The tumor suppressor p53 is suggested to have a negative role on VEGF expression (Bouvet et al, 1998;Fontanini et al, 1998;Mukhopadhyay et al, 1995). At the molecular level, it has been shown that p53 inhibits HIF1 activity by targeting the HIF1a subunit for ubiquitination and proteasomal degradation (Ravi et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

TAp63γ (p51A) and dNp63α (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression

2002

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Tumor suppressor p53 has been shown to repress expression of vascular endothelial growth factor (VEGF), an endothelial cell-speci®c mitogen and a key mediator of tumor angiogenesis. The p63 gene, recently identi®ed as a p53-relative, encodes multiple isoforms with structural and functional similarities and di erences from p53. In this study, we show the evidence that the two major isoforms of the p63 gene, TAp63g (p51A) and dNp63a (p73L), represses and upregulates VEGF expression, respectively, on transcription and protein levels. Transient transfection assays show that a hypoxia-inducible factor (HIF) 1 binding site within the VEGF promoter region is responsible for both upregulation and repression by dNp63a and by TAp63g, respectively, of the VEGF promoter activity. We also show that TAp63g targets HIF1a for promoting proteasomal degradation but that dNp63a targets HIF1a for stabilization. Mammalian two-hybrid assays show that HIF1a-dependent transcription is repressed by TAp63g as well as by p53, whereas it is upregulated by dNp63a in collaboration with a transcription coactivator p300. Our data also show that dNp63a acts as a dominant-negative reagent toward both p53-and TAp63g-mediated degradation of HIF1a and repression of HIF1a-dependent transcription. These results suggest that p63 is involved in the regulation of the VEGF gene expression and that modulation of VEGF expression by TAp63g and dNp63a is closely correlated with their distinct roles on the regulation of HIF1a stability.

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“…This contrasts with reports of adenoviral gene transfer in which cellular infiltrates about transfected cells are regularly observed. [12][13]22 The failure of the complex to induce a 'danger' signal in the vicinity of the transfected cells may reduce the host's immune response to the transgene.…”

Section: Discussionmentioning

confidence: 99%

Defining strategies to extend duration of gene expression from targeted compacted DNA vectors

et al. 2004

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Gene transfer complexes containing poly-L-lysine (poly-K) and DNA with ligands directed at the serpin enzyme complex receptor (sec-R) deliver reporter genes to receptor-bearing cells in vivo. Expression lasts for about 30 days, when complexes containing long-chain poly-K are used. Extending the duration of expression would be desirable if correction of genetic defects is the goal. To test whether the mechanism by which expression is extinguished was due to an immune response to the transgene, or the loss of the transgene, we conducted two experiments. In the first, we injected sec-Rtargeted lacZ complexes intravenously (i.v.) into mice genetically engineered to express this gene briefly during development. These mice, who should recognize the protein as 'self', also extinguished lacZ expression after 30 days. In a second experiment, we injected immunodeficient animals with sec-R-targeted human factor IX complexes. A similar temporal pattern of expression was observed in Rag-1 À/À mice, in whom expression also extinguished by 40 days. Moreover, factor IX plasmid DNA was detected in the lung and spleen 50 days after injection of complexes, suggesting that not all cells which had taken up the transgene had been destroyed. Thus, the host's immune response to the transgene may not account for the loss of reporter gene expression from these molecular conjugates. We further tested whether repeat administration of sec-R-targeted complexes will be limited by host immune responses. Mice were pre-dosed twice with sec-R-targeted complexes containing lacZ over a 40-day period. We then injected the animals i.v. with sec-R-targeted human factor IX complexes and measured gene expression and antibody production. Although 14 of 36 animals displayed low-titer antibodies to the ligand in targeted complex, expression levels were unaffected compared with virgin dosing. When the complexes were administered three times intranasally (n ¼ 10), no antibodies against the complex were detected in blood. Plasma from mice dosed with saline, nontargeted complex or naked DNA did not react with the ligand, ligand-poly K conjugate or targeted complex. All animals exhibiting human factor IX expression developed antibodies to that transgene by 21 days. Thus, at least three repeat administrations of sec-R-directed molecular conjugates are possible, provided that immune responses to the transgene itself are not limiting.

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Suppression of the immune response to an adenovirus vector and enhancement of intratumoral transgene expression by low-dose etoposide

Cited by 65 publications

References 14 publications

Adeno-associated virus serotype 9-mediated pulmonary transgene expression: effect of mouse strain, animal gender and lung inflammation

Adeno-associated virus serotype 9-mediated pulmonary transgene expression: effect of mouse strain, animal gender and lung inflammation

TAp63γ (p51A) and dNp63α (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression

Defining strategies to extend duration of gene expression from targeted compacted DNA vectors

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