Stent-based delivery of adeno-associated viral vectors with sustained vascular transduction and iNOS-mediated inhibition of in-stent restenosis
- Select a language for the TTS:
- UK English Female
- UK English Male
- US English Female
- US English Male
- Australian Female
- Australian Male
- Language selected: (auto detect) - EN
Play all audios:
In-stent restenosis remains an important clinical problem in the era of drug eluting stents. Development of clinical gene therapy protocols for the prevention and treatment of in-stent
restenosis is hampered by the lack of adequate local delivery systems. Herein we describe a novel stent-based gene delivery platform capable of providing local arterial gene transfer with
adeno-associated viral (AAV) vectors. This system exploits the natural affinity of protein G (PrG) to bind to the Fc region of mammalian IgG, making PrG a universal adaptor for surface
immobilization of vector-capturing antibodies (Ab). Our results: 1) demonstrate the feasibility of reversible immobilization of AAV2 vectors using vector tethering by AAV2-specific Ab
appended to the stent surface through covalently attached PrG, 2) show sustained release kinetics of PrG/Ab-immobilized AAV2 vector particles into simulated physiological medium in vitro and
site-specific transduction of cultured cells, 3) provide evidence of long-term (12 weeks) arterial expression of luciferase with PrG/Ab-tethered AAV2Luc, and 4) show anti-proliferative
activity and anti-restenotic efficacy of stent-immobilized AAV2iNOS in the rat carotid artery model of stent angioplasty.
This work was supported in part by research grants from the National Heart, Lung and Blood Institute including R56-HL 72108, R01HL137762, R01-HL111118, R21- HL131016. Support was also
provided by the William J Rashkind Endowment and Erin's Fund of the Children's Hospital of Philadelphia. PTA catheters were kindly provided by NuMed (Hopkinton, NY, USA). Authors wish to
acknowledge Ms. Susan Kerns for preparing the manuscript materials for publication.
The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
I Fishbein, D T Guerrero, I S Alferiev, J B Foster, N G Minutolo, M Chorny, A M Monteys & R J Levy
The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
I Fishbein, I S Alferiev, N G Minutolo, M Chorny, K H Driesbaugh, C Nagaswami & R J Levy
Supplementary Information accompanies this paper on Gene Therapy website
Anyone you share the following link with will be able to read this content: