Innovative Erythrocyte-based Carriers for Gene Delivery in Porcine Vascular Smooth Muscle Cells: Basis for Local Therapy to Prevent Restenosis
Maria Giovanna Trivella,
Vascular restenosis is affecting 30-40% of patients treated by percutaneous coronary angioplasty (PTCA). The
advent of stenting reduced but not abolished restenosis. The introduction of drug eluting stent (DES) further reduced
restenosis, but impaired endothelization exposed to intracoronary thrombosis as late adverse event.
It is widely accepted that the endothelial denudation and coronary wall damages expose Vascular Smooth Muscle Cells
(VSMC) to multiple growth factors and plasma circulating agents thus activating migration and proliferative pathways
leading to restenosis.
Among the major players of this processes, phosphorylated Elk-1, forming the Elk-1/SRF transcription complex, controls
the expression of a different set of genes responsible for cell proliferation. Therefore, it is feasible that gene-specific
oligonucleotide therapy targeting VSMC migration and proliferation genes can be a promising therapeutic approach.
While a plethora of vehicles is suitably working in static in vitro cultures, methods for in vivo delivery of oligonucleotides
are still under investigation. Recently, we have patented a novel erythrocyte-based drug delivery system with high
capability to fuse with targeted cells thus improving drug bioavailability at the site of action. Here, the potential of these
engineered porcine erythrocytes to deliver a synthetic DNA Elk-1 decoy inside syngenic porcine VSMC was tested. The
results of this study indicate that Elk-1 decoy is actually able to inhibit cell proliferation and migration of VSMC. Our
data also suggest that erythrocyte-based carriers are more efficient in delivering these oligonucleotides in comparison to
conventional vehicles. As a consequence, a lower dose of Elk-1 decoy, delivered by engineered erythrocytes, was
sufficient to inhibit cell growth and migration.
This approach represents the translational step to reach in vivo experiments in pigs after PTCA and/or stent implantation
where oligonucleotide drugs will be site-specific administered by using erythrocyte-based carriers to prevent restenosis.
Keywords: Vascular Smooth Muscle Cells, DNA Oligonucleotide decoy, gene therapy, erythrocyte-based drug delivery
system, target therapy, biotherapy delivery, endothelial layer, hyperplasia
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