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EXPERIMENTAL STUDY

Intramural coronary delivery of advanced antisense oligonucleotides reduces neointimal formation in the porcine stent restenosis model

Nicholas N. Kipshidze, MD, PhD, FACC^*,*, Han-Soo Kim, MD, FACC, Patrick Iversen, PhD, Hamid A. Yazdi, MD, Balram Bhargava, MD, Gishel New, MD, FACC^*, Roxana Mehran, MD, FACC^*, Fermin Tio, MD, Christian Haudenschild, MD^||, George Dangas, MD, PhD, FACC^*, Gregg W. Stone, MD, FACC^*, Sriram Iyer, MD, FACC^*, Gary S. Roubin, MD, PhD, FACC^*, Martin B. Leon, MD, FACC^* and Jeffrey W. Moses, MD, FACC^*

^* Lenox Hill Heart and Vascular Institute and Cardiovascular Research Foundation, New York, New York, USA
Cardiology Research Institute, Washington, DC, USA
AVI BioPharma, Portland, Oregon, USA
Biomedical Research Foundation of South Texas, San Antonio, Texas, USA
^|| American Red Cross, Jerome Holland Laboratories, Rockville, Maryland, USA

Manuscript received March 12, 2001; revised manuscript received February 21, 2002, accepted February 27, 2002.

^* Reprint requests and correspondence: Dr. Nicholas Kipshidze, Lenox Hill Heart and Vascular Institute, 130 East 77th Street, Black Hall-9th Floor, New York, New York 10021.
nkipshidze{at}lenoxhill.net

OBJECTIVES: We evaluated the long-term influence of intramural delivery of advanced c-myc neutrally charged antisense oligonucleotides (Resten-NG) on neointimal hyperplasia after stenting in a pig model.

BACKGROUND: Neointimal hyperplasia after percutaneous coronary interventions is one of the key components of the restenotic process. The c-myc is a critical cell division cycle protein involved in the formation of neointima.

METHODS: In short-term experiments, different doses (from 500 µg to 5 mg) of Resten-NG or saline were delivered to the stent implantation site with an infiltrator delivery system (Interventional Technologies, San Diego, California). Animals were euthanized at 2, 6 and 18 h after interventions, and excised vessels were analyzed for c-myc expression by Western blot. In long-term experiments, either saline or a dose of 1, 5 or 10 mg of Resten-NG was delivered in the same fashion, and animals were euthanized at 28 days after the intervention.

RESULTS: Western blot analysis demonstrated inhibition of c-myc expression and was dose dependent. Morphometry showed that the intimal area was 3.88 ± 1.04 mm² in the control. There was statistically significant reduction of intimal areas in the 5 and 10 mg groups (2.01 ± 0.66 and 1.95 ± 0.91, respectively, p < 0.001) but no significant reduction in the 1 mg group (2.81 ± 0.56, p > 0.5) in comparison with control.

CONCLUSIONS: This study demonstrated that intramural delivery of advanced c-myc neutrally charged antisense morpholino compound completely inhibits c-myc expression and dramatically reduces neointimal formation in a dose dependent fashion in a porcine coronary stent restenosis model, while allowing for complete vascular healing.

Abbreviations and Acronyms   H&E   hematoxylin and eosin   IBC   Infiltrator Balloon Catheter   PMO   phosphorothioate morpholino oligomers   PTCA   percutaneous transluminal coronary angioplasty   SMC   smooth muscle cell

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