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Intramural delivery of recombinant

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Intramural delivery of recombinant

  1. 1. Intramural Delivery of Recombinant Apolipoprotein A-I Milano /Phospholipid Complex (ETC-216) Inhibits In-stent Stenosis in Porcine Coronary Arteries Sanjay Kaul, Vladimir Rukshin, Raul Santos, Babak Azarbal, *Charles L. Bisgaier, *Jan Johansson, Vivian T. Tsang, Kuang-Yuh Chyu, James Mirocha, Bojan Cercek, Prediman K. Shah Atherosclerosis Research Center, Cedars-Sinai Burns & Allen Research Institute, Division of Cardiology, Cedars-Sinai Medical Center and *Esperion Therapeutics
  2. 2. • Mutant Apo A-I • Arginine to cysteine substitution at 173 position • Transmitted as an autosomal dominant trait by a single mating couple in Italy in the 18th century • Confers protection from vascular disease despite elevated triglycerides and low HDL levels • Associated with longevity Apolipoprotein A-IMilano
  3. 3. • Antiatherogenic effects Inhibits progression of atherosclerosis and promotes regression of atherosclerosis in atherosclerosis-susceptible transgenic mice, the apo E null mice (Shah et al, Circulation. 1998; 97: 780–5) • Vascular response to injury Reduction in neointimal hyperplasia in balloon-injured ileofemoral arteries of cholesterol-fed rabbits (Ameli et al, Circulation. 1994;90:1935-41) • After repeated systemic administration of Apo A-IMilano 50 mg/kg IV in rabbits (5 injections every other day) 20-80 mg/kg IV in apo E null mice (18 injections every other day) Vasculoprotective Effects of Apo A-IMilano
  4. 4. • Utilizing a local intramural drug delivery approach via the Infiltrator catheter, we sought to examine the effects of recombinant apolipoprotein A-IMilano/1-palmitoyl,2- oleoyl phosphatidylcholine complex (ETC-216) on luminal narrowing in a porcine coronary artery stent Aim of the Study
  5. 5. • Intramural delivery into the coronary vessel wall provides for enhanced delivery efficiency, minimizes agent loss into the systemic circulation, thereby resulting in lower doses, longer duration of activity, and improved overall effectiveness in modulating coronary arterial response to Hypothesis
  6. 6. Experimental Protocol • Coronary Stent Overstretch Injury 3.0-4.0 x 15 mm GFX Stent inflated at 8-12 atm x3 (S:A ~ 1.3:1) • Animal Groups (Adult farm swine: 25-30 kg) Group I: apo A-1M (n=6, 12 arteries) Group II: vehicle control (n=6, 12 arteries) • Histomorphometry Perfusion-fixation, H&E and special stain, computerized morphometry Day 0 28 Intramural local drug delivery Angio Coronary Injury Angio Histomorphometry
  7. 7. Treatment Interventions • Reconstituted HDL (ETC-216) Recombinant mutant apolipoprotein A-IMilano (14mg/ml) complexed with 1-palmitoyl, 2-oleoyl phosphatidylcholine (POPC, 13mg/ml) • Vehicle Sucrose-mannitol • Dose and Administration 0.19 mg/kg x1 intramural (infusate volume ~ 0.4ml), prior to injury
  8. 8. Quantitative Coronary Angiographic Data 1.5 2 2.5 3 3.5 4 4.5 MeanLumenDiameter (mm) Acute Lumen Gain Lumen Loss Baseline SacrificePost-Injury Mean+SD N=12 ETC-216 Control *P=0.01 Lumen Loss Index 21+22% 43+13% *
  9. 9. Histologic Sections (RCA) Proximal Segment Distal Segment Control ETC-216
  10. 10. Histomorphometric Data 5.1 1.7 3.3 1.5 0 2 4 6 8 Injury ScoreIntima:Media Ratio Mean+SD N=12 P=0.003 Area(mm2 ) Control ETC-216 6.7 1.4 2.4 2.1 5.2 1.6 1.9 3.7 0 2 4 6 8 10 LumenIntima Media Adventitia P=0.02 P=0.02
  11. 11. 0 1 2 3 4 0.0 2.5 5.0 7.5 10.0 Injury Score Lumen Area (mm2 ) 0 1 2 3 4 0 5 10 15 Injury Score mm2 Neointimal Area (mm2 ) 0 1 2 3 4 0.0 0.5 1.0 1.5 Injury Score Stenosis Index 0 0 1 2 Injury Score 1 2 3 4 Neointimal Thickness (mm) P=0.004 P=0.003 P=0.001 P=0.003 Histomorphometric Data
  12. 12. • A single intramural administration of very low- dose ETC-216 produced a significant reduction in injury-induced luminal narrowing in the porcine coronary stent overstretch injury model through inhibition of intimal hyperplasia Conclusion
  13. 13. Implication •The data show that local intracoronary delivery of ETC-216 may be useful to prevent restenosis after coronary stenting

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