Persistent liver expression of murine apoA-l using vectors based on adeno-associated viral vectors serotypes 5 and 1.

Abstract

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.

• Authors: Ken Kitajima, Dawn H L Marchadier, Haim Burstein, Daniel J Rader
• Journal: Atherosclerosis (Atherosclerosis) Vol. 186 Issue 1 Pg. 65-73 (May 2006) ISSN: 0021-9150 [Print] Ireland
• PMID: 16099465 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• RNA, Messenger

Topics

• Animals
• Apolipoprotein A-I (biosynthesis, genetics)
• Coronary Disease (genetics, metabolism, prevention & control)
• Dependovirus (classification, genetics)
• Disease Models, Animal
• Female
• Gene Expression
• Gene Transfer Techniques
• Genetic Vectors (administration & dosage)
• Liver (metabolism)
• Mice
• Mice, Inbred C57BL
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Serotyping