title: Intramural coronary delivery of advanced antisense oligonucleotides reduces neointimal formation in the porcine stent restenosis model.
abstract: OBJECTIVE
  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 microg 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 mm(2) 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.
authors.affiliation: Lenox Hill Heart and Vascular Institute and Cardiovascular Research Foundation, New York, New York 10021, USA. nkipshidze@lenoxhill.net
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Kipshidze
authors.forename: Han Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Patrick
authors.initials: P
authors.lastname: Iversen
authors.forename: Hamid A
authors.initials: HA
authors.lastname: Yazdi
authors.forename: Balram
authors.initials: B
authors.lastname: Bhargava
authors.forename: Gishel
authors.initials: G
authors.lastname: New
authors.forename: Roxana
authors.initials: R
authors.lastname: Mehran
authors.forename: Fermin
authors.initials: F
authors.lastname: Tio
authors.forename: Christian
authors.initials: C
authors.lastname: Haudenschild
authors.forename: George
authors.initials: G
authors.lastname: Dangas
authors.forename: Gregg W
authors.initials: GW
authors.lastname: Stone
authors.forename: Sriram
authors.initials: S
authors.lastname: Iyer
authors.forename: Gary S
authors.initials: GS
authors.lastname: Roubin
authors.forename: Martin B
authors.initials: MB
authors.lastname: Leon
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Moses
mesh_terms: D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D002455:Cell Division / Q000502:physiology; D003324:Coronary Artery Disease / Q000473:pathology*; D023903:Coronary Restenosis / Q000473:pathology*; D005260:Female; D005352:Fibromuscular Dysplasia / Q000473:pathology*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors; D015607:Stents; D013552:Swine; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc