Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954

Poorter, Jolanda J. de; Tolboom, Tanja C. A.; Rabelink, Martijn J. W. E.; Pieterman, Elsbet J.; Hoeben, Rob C.; Nelissen, Rob G H H; Huizinga, Tom W J

doi:10.1002/jgm.795

Cited by 17 publications

(10 citation statements)

References 24 publications

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“…Ideally, the agent could be applied locally, thus minimizing systemic effects [146]. Systemic blocking or interference with NF-κB activity would undoubtedly impair the normal host immune system.…”

Section: Discussionmentioning

confidence: 99%

Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-κB as a therapeutic target

Lin¹,

Tamaki²,

Pajarinen³

et al. 2014

Acta Biomaterialia

183

150

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Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-κB. NF-κB activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6, MCP1, etc. In addition, NF-κB activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-α or IL-1β) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core IκB/IKKα/β/NF-κB signaling pathway in the local environment, however, the timing, dose, and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-κB activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis.

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Section: Discussionmentioning

confidence: 99%

Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-κB as a therapeutic target

Lin¹,

Tamaki²,

Pajarinen³

et al. 2014

Acta Biomaterialia

183

150

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“…Localized delivery of substrate-immobilized gene vectors has gained attention as a clinically translatable approach for the delivery of therapeutic transgenes in the setting of medical conditions that require implantation of temporary or permanent bioprosthetic devices, such as urological, bronchial and endovascular stents, orthopedic implants and pacemakers [38-41]. The added benefit of gene therapy provided in combination with medical device implantation is two-fold: 1) to increase the therapeutic effectiveness of the implant and 2) to promote its integration into the host tissues.…”

Section: Discussionmentioning

confidence: 99%

Adenoviral vector tethering to metal surfaces via hydrolyzable cross-linkers for the modulation of vector release and transduction

et al. 2013

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The use of arterial stents and other medical implants as a delivery platform for surface immobilized gene vectors allows for safe and efficient localized expression of therapeutic transgenes. In this study we investigate the use of hydrolysable cross-linkers with distinct kinetics of hydrolysis for delivery of gene vectors from polyallylamine bisphosphonate-modified metal surfaces. Three cross-linkers with the estimated t1/2 of ester bonds hydrolysis of 5, 12 and 50 days demonstrated a cumulative 20%, 39% and 45% vector release, respectively, after 30 days exposure to physiological buffer at 37°C. Transgene expression in endothelial and smooth muscles cells transduced with substrate immobilized adenovirus resulted in significantly different expression profiles for each individual cross-linker. Furthermore, immobilization of adenoviral vectors effectively extended their transduction effectiveness beyond the initial phase of release. Transgene expression driven by adenovirus-tethered stents in rat carotid arteries demonstrated that a faster rate of cross-linker hydrolysis resulted in higher expression levels at day 1, which declined by day 8 after stent implantation, while inversely, slower hydrolysis was associated with increased arterial expression at day 8 in comparison with day 1. In conclusion, adjustable release of transduction-competent adenoviral vectors from metallic surfaces can be achieved, both in vitro and in vivo, through surface immobilization of adenoviral vectors using hydrolysable cross-linkers with structure-specific release kinetics.

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“…Neither part of this technique has been described so far in the literature. As was shown by our group, the interface tissue can be transduced and killed in vitro (de Poorter et al, 2005) and in vivo in animals (Goossens et al, 1999) by the viral vector HAdV-5-ntr in combination with the prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954). To evaluate this concept of removal of interface tissue by gene-directed therapy and cement refixation of the prosthesis, a phase 1/2 clinical trial was performed in 12 elderly patients with considerable comorbidity.…”

Section: Introductionmentioning

confidence: 92%

Gene Therapy and Cement Injection for Restabilization of Loosened Hip Prostheses

et al. 2008

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Loosening of orthopedic hip prostheses is an increasing health problem. In elderly patients with comorbidity,revision surgery may lead to high mortality rates. A less invasive surgical technique is therefore required to reduce these patient risks. To this end a percutaneous gene therapy approach was designed to destroy the periprosthetic loosening membrane, and enable refixing of the hip prosthesis with percutaneous bone cement injections under radiological guidance. In this phase 1/2 dose-escalating gene therapy clinical trial, 12 patients were treated. Toxicity and hip function variables were monitored up to 6 months posttreatment. All patients completed the study and no dose-limiting toxicity was observed. Improvement in walking distance, independence,and pain was demonstrated particularly in patients receiving 3 x 10(10) and 1 x 10(11) viral particles. Taken together, these data show that this gene therapy approach targeted at the interface membrane around a loosened hip prosthesis is a feasible treatment option for elderly patients for whom surgical intervention is not appropriate.

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Towards gene therapy in prosthesis loosening: efficient killing of interface cells by gene-directed enzyme prodrug therapy with nitroreductase and the prodrug CB1954

Abstract: From these data we conclude that HAdV-5-based vectors carrying nitroreductase can be used to sensitize interface tissue. Instead of contrast medium the clinical protocol will use an alternative visualization procedure.

Cited by 17 publications

References 24 publications

Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-κB as a therapeutic target

Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-κB as a therapeutic target

Adenoviral vector tethering to metal surfaces via hydrolyzable cross-linkers for the modulation of vector release and transduction

Gene Therapy and Cement Injection for Restabilization of Loosened Hip Prostheses

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