title: Local Vascular Gene Therapy With Apolipoprotein A-I to Promote Regression of Atherosclerosis.
abstract: OBJECTIVE
  Gene therapy, delivered directly to the blood vessel wall, could potentially prevent atherosclerotic lesion growth and promote atherosclerosis regression. Previously, we reported that a helper-dependent adenoviral (HDAd) vector expressing apolipoprotein A-I (apoA-I) in carotid endothelium of fat-fed rabbits reduced early (4 weeks) atherosclerotic lesion growth. Here, we tested whether the same HDAd-delivered to the existing carotid atherosclerotic lesions-could promote regression.
  
  
  RESULTS
  Rabbits (n=26) were fed a high-fat diet for 7 months, then treated with bilateral carotid gene transfer. One carotid was infused with an HDAd expressing apoA-I (HDAdApoAI) and the other with a control nonexpressing HDAd (HDAdNull). The side with HDAdApoAI was randomized. Rabbits were then switched to regular chow, lowering their plasma cholesterols by over 70%. ApoA-I mRNA and protein were detected in HDAdApoAI-transduced arteries. After 7 weeks of gene therapy, compared with HDAdNull-treated arteries in the same rabbits, HDAdApoAI-treated arteries had significantly less vascular cell adhesion molecule-1 expression (28%; P=0.04) along with modest but statistically insignificant trends toward decreased intimal lesion volume, lipid and macrophage content, and intercellular adhesion molecule-1 expression (9%-21%; P=0.1-0.4). Post hoc subgroup analysis of rabbits with small-to-moderate-sized lesions (n=20) showed that HDAdApoAI caused large reductions in lesion volume, lipid content, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression (30%-50%; P≤0.04 for all). Macrophage content was reduced by 30% (P=0.06). There was a significant interaction (P=0.02) between lesion size and treatment efficacy.
  
  
  CONCLUSIONS
  Even when administered on a background of aggressive lowering of plasma cholesterol, local HDAdApoAI vascular gene therapy may promote rapid regression of small-to-moderate-sized atherosclerotic lesions.
authors.affiliation: From the Department of Medicine, University of Washington School of Medicine, Seattle.
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wacker
authors.affiliation: From the Department of Medicine, University of Washington School of Medicine, Seattle.
authors.forename: Nagadhara
authors.initials: N
authors.lastname: Dronadula
authors.affiliation: From the Department of Medicine, University of Washington School of Medicine, Seattle.
authors.forename: Jingwan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Medicine, University of Washington School of Medicine, Seattle. ddichek@uw.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Dichek
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D017536:Carotid Artery, Common / Q000378:metabolism* / Q000473:pathology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular; D058426:Neointima; D058226:Plaque, Atherosclerotic; D011817:Rabbits; D012074:Remission Induction; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016632:Apolipoprotein A-I; D008055:Lipids; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1
keywords: apolipoprotein A-I; atherosclerosis; carotid arteries; genetic therapy; macrophages; rabbits