Biomedical Engineering Reference
In-Depth Information
Novel Technologies for DES
Stents for Delivery of Gene Therapy
Stents represent an attractive method for localized gene delivery as they provide a
platform for prolonged gene elution and efficient transduction of opposed arterial
walls. This gene delivery strategy has the potential to decrease the systemic spread
of the viral vectors and hence a reduced host immune response. Both synthetic and
naturally occurring stent coatings have the potential to enable prolonged gene elu-
tion with no significant adverse reaction.
An adenovirus vector is capable of expressing the tissue inhibitor of
metalloproteinase-3 (RAdTIMP-3) and inhibits neointima formation in blood
vessels. An eluting stent technology has been developed to deliver RAdTIMP-3
during stenting of pig coronary arteries (Johnson et al.
2005
). Binding of virus to
and elution from stents and transduction of pig coronary arteries were confirmed
using beta-galactosidase as a reporter gene in vitro and in vivo. Deployment of
RAdTIMP-3-coated stents increased apoptosis and reduced neointimal cell density,
but did not increase inflammation or proliferation. This study demonstrates the
feasibility of adenovirus-coated stent technology and indicates the potential of
TIMP-3 to produce significant inhibition of in-stent neointima formation.
Gene therapy to treat in-stent restenosis by using gene vector delivery from the
metallic stent surfaces has not been previously demonstrated. A study has investi-
gated the hypothesis that metal-bisphosphonate binding can enable site-specific
gene vector delivery from metal surfaces. Exposure to aqueous solutions of poly-
allylamine bisphosphonate (PAA-BP) results in the formation of a monomolecular
bisphosphonate layer on metal alloy surfaces (steel, nitinol, and cobalt-chromium),
as demonstrated by x-ray photoelectron spectroscopy. Surface-bound PAA-BP
enabled adenoviral (Ad) tethering due to covalent thiol-binding of either anti-Ad
antibody or a recombinant Ad-receptor protein, D1 (Fishbein et al.
2006
). In arte-
rial smooth muscle cell cultures, alloy samples configured with surface-tethered Ad
were demonstrated to achieve site-specific transduction with a reporter gene - green
fluorescent protein (GFP). Rat carotid stent angioplasties using metal stents
exposed to aqueous PAA-BP and derivatized with anti-knob antibody or D1
resulted in extensive localized Ad-GFP expression in the arterial wall. In another
study with a model therapeutic vector, Ad-inducible nitric oxide synthase (iNOS)
attached to the bisphosphonate-treated metal stent surface via D1, significantly
inhibited restenosis. Therefore, effective gene vector delivery from metallic stent
surfaces can be achieved by using this approach.
Both adeno-associated virus type 2 (AAV2) and adenovirus, commonly used for
gene transfer applications, can achieve prolonged and localized gene delivery to the
vessel wall, using stents as delivery platforms. AdbGal and AAV2bGal have been
used to coat BiodivYsio stents with matrix HI coating (Abbott Vascular Devices,
Galway, Ireland). After balloon injury, external iliac arteries of New Zealand White
rabbits were stented and reverse transcription-PCR was used to assess viral spread
(Sharif et al.
2006
). Expression of LacZ was demonstrated with both vectors at
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