Persistent liver expression of murine apoA-l using vectors based on adeno-associated viral vectors serotypes 5 and 1.
Plasma levels of high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-l (apoA-l) are inversely related to risk for coronary heart disease. Overexpression of apoA-l inhibits atherosclerosis in animal models. A method of stably expressing apoA-l using somatic gene transfer would be of interest. Pseudotyped adeno-associated virus (AAV) vectors comprised of inverted terminal repeats from AAV serotype 2 have been used for liver-directed gene transfers. We hypothesized that liver-directed gene transfer of apoA-l using vectors based on AAV serotypes 1 and 5 would result in higher-level, prolonged expression of apoA-l and increased HDL-C. To test this hypothesis we injected apoA-l-/- mice via the tail vein with either AAV2, AAV1 or AAV5 vectors encoding the murine apoA-l cDNA driven by the liver-specific thyroxine binding globulin promoter. Plasma levels of murine apoA-l and HDL-C were highest in mice injected with the AAV1-based vector and lowest in mice injected with the AAV2-based vector. Expression of apoA-l was stable up to 1 year after vector injection. These results indicate that AAV5 and AAV1 are more effective vectors for achieving higher levels of stable transgene expression of apoA-l after liver-directed gene transfer than AAV2. Furthermore, AAV1-based vectors generate higher apoA-l levels than AAV5-based vectors. It is possible that the levels of expression achieved using these vectors will be therapeutic in preventing atherosclerosis.
Kitajima
Ken
K
Institute for Translational Medicine and Therapeutics, University of Pennsylvania Medical Center, 654 BRBII/III Labs, 421 Curie Blvd, Philadelphia, PA 19104-6160, USA.
Marchadier
Dawn H L
DH
Burstein
Haim
H
Rader
Daniel J
DJ
D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000235:genetics*; D003327:Coronary Disease / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D000229:Dependovirus / Q000145:classification / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012703:Serotyping
D016632:Apolipoprotein A-I; D012333:RNA, Messenger