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

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

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1686-1691
Number of pages6
JournalJournal of the American College of Cardiology
Volume39
Issue number10
DOIs
StatePublished - May 15 2002
Externally publishedYes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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