Abstract

A synergistic impact of research in the fields of post-angioplasty restenosis, drug-eluting stents and vascular gene therapy over the past 15 years has shaped the concept of gene-eluting stents. Gene-eluting stents hold promise of overcoming some biological and technical problems inherent to drug-eluting stent technology. As the field of gene-eluting stents matures it becomes evident that all three main design modules of a gene-eluting stent: a therapeutic transgene, a vector and a delivery system are equally important for accomplishing sustained inhibition of neointimal formation in arteries treated with gene delivery stents. This review summarizes prior work on stent-based gene delivery and discusses the main optimization strategies required to move the field of gene-eluting stents to clinical translation.

Highlights

  • Minimal requirements for Gene-Eluting Stents (GES) function and performanceThe design requirements for GES share several characteristics with drug-eluting stents (DES) platforms

  • A synergistic impact of research in the fields of post-angioplasty restenosis, drug-eluting stents and vascular gene therapy over the past 15 years has shaped the concept of gene-eluting stents

  • Gene therapy can attain a longer lasting therapeutic modification of vascular substrate; second, gene interventions allow for selective inhibition of SMC proliferation and migration while maintaining and even enhancing endothelial re-growth; third, the underlying atherosclerotic process can be addressed; and fourth, a modulation of the biological activity of gene-eluting stents can be achieved with systemically administered low molecular weight compounds

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Summary

Minimal requirements for GES function and performance

The design requirements for GES share several characteristics with DES platforms Deliverability of both types of devices should not be compromised by the accommodation of a therapeutic agent and its matrix on the stent struts. Since the medial and neointimal SMC proliferation starts no earlier than 1 week after stent deployment in human and higher animal models [13], the target cell population is not yet present at the time of vascular injury. This fact argues for at least 2–3 week-long release period of a transduction competent gene vector from the stent, posing additional requirements to GES technology related to extended vector stability in vivo. The 1–2 orders of magnitude size difference between LMW drugs and gene vectors dictates use of different matrices to enable timely release of a therapeutic agent from a stent platform, affecting the predominant mechanism of the agent release (diffusion vs matrix degradation)

Conceptual Technologies in GES Design
Surface immobilization of gene vectors on coatless metal substrate
Magnetic stent targeting
Reporter Studies and Pharmacokinetics of Transgene Expression
GES targeting inflammatory cell recruitment
GES targeting thrombus formation in stented arteries
Stents targeting nitric oxide production
Findings
Conclusions

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