Intramural coronary delivery of advanced antisense oligonucleotides reduces neointimal formation in the porcine stent restenosis model.
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.
Kipshidze
Nicholas N
NN
Lenox Hill Heart and Vascular Institute and Cardiovascular Research Foundation, New York, New York 10021, USA. nkipshidze@lenoxhill.net
Kim
Han Soo
HS
Iversen
Patrick
P
Yazdi
Hamid A
HA
Bhargava
Balram
B
New
Gishel
G
Mehran
Roxana
R
Tio
Fermin
F
Haudenschild
Christian
C
Dangas
George
G
Stone
Gregg W
GW
Iyer
Sriram
S
Roubin
Gary S
GS
Leon
Martin B
MB
Moses
Jeffrey W
JW
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*
D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc