Gene transfer into rabbit arteries with adeno-associated virus and adenovirus vectors.

Gene transfer offers considerable potential for altering vessel wall physiology and intervention in vascular disease. Therefore, there is great interest in developing optimal strategies and vectors for efficient, targeted gene delivery into a vessel wall. We studied adeno-associated viruses (AAV; 9 x 10(8) to 4 x 10(9) TU/ml) for their usefulness to transduce rabbit arteries in vivo in comparison with adenoviruses (Adv; 1 x 10(9) to 1 x 10(10) pfu/ml). 100 microl of viruses or placebo solution were injected intraluminally into transiently isolated carotid segments. In normal arteries AAV transduced mainly medial smooth muscle cells (SMC) while Adv transduced exclusively endothelial cells (EC). Mechanical injury to EC layer and internal elastic lamina enabled Adv to penetrate and transduce medial SMC. Transgene expression in EC after the AAV-mediated gene transfer was very low. The use of the EC-specific Tie-1 promoter did not lead to specific transgene expression in EC. Transgene expression in SMC persisted for at least 100 days after the AAV treatment whereas the Adv-mediated effect diminished in 14 days. AAV caused only a modest increase in EC VCAM-1 expression and proliferation rate of vascular cells as compared with the mock-treated arteries while Adv caused an extensive inflammatory cell infiltration, VCAM-1 expression, vascular cell proliferation and morphological damages. Significant differences were observed between the AAV and the Adv vectors in their patterns of arterial transduction and consequent inflammatory responses. These distinct properties may be utilized for different applications in vascular biology research and gene therapy for cardiovascular diseases.

Gruchała M ，Bhardwaj S ，Pajusola K ，Roy H ，Rissanen TT ，Kokina I ，Kholová I ，Markkanen JE ，Rutanen J ，Heikura T ，Alitalo K ，Büeler H ，Ylä-Herttuala S ... -  《JOURNAL OF GENE MEDICINE》

Gene delivery to the vasculature mediated by low-titre adeno-associated virus serotypes 1 and 5.

Sen S ，Conroy S ，Hynes SO ，McMahon J ，O'Doherty A ，Bartlett JS ，Akhtar Y ，Adegbola T ，Connolly CE ，Sultan S ，Barry F ，Katusic ZS ，O'Brien T ... -  《JOURNAL OF GENE MEDICINE》

A CMV-actin-globin hybrid promoter improves adeno-associated viral vector gene expression in the arterial wall in vivo.

Adeno-associated virus (AAV) vectors are attractive tools for direct intralumenal arterial gene transfer in interventional cardiology or cardiovascular surgery, but clinical application has been constrained by poor gene expression in this setting. To improve arterial wall gene expression, a hybrid promoter consisting of a cytomegalovirus (CMV) immediate-early enhancer, a chicken beta-actin transcription start site, and a rabbit beta-globin intron (CAG promoter) was substituted for the Rous sarcoma virus (RSV) promoter in an AAV type 2 vector with an alkaline phosphatase (AP) reporter gene. Intralumenal transduction of rabbit carotid arteries by an AAV2 vector containing a CAG promoter resulted in gene expression in a mean of > or = 80% of the lumenal area at 14 days following exposure, compared to < or = 25% gene-expressing area with the RSV promoter-based control vector. The high prevalence of gene expression was maintained at 3, 7, 14, and 28 days. Importantly, in carotid arteries transduced with the CAG promoter, gene product expression was readily visible by the third day following transduction whereas gene expression was rarely seen before day 10 using the RSV promoter in the same animal model. On histology, AP gene expression was predominantly in vascular smooth muscle cells although some endothelial cell expression was also present. Substituting the CAG for the RSV promoter results in widespread gene expression, demonstrating efficient arterial wall transduction by AAV2 vectors. This finding plus the early time to gene expression hold promise for AAV vectors as agents for direct intralumenal arterial wall gene delivery during cardiovascular interventions.

Nitta Y ，Kawamoto S ，Halbert C ，Iwata A ，Miller AD ，Miyazaki J ，Allen MD ... -  《-》

Adeno-associated virus vectors for vascular gene delivery.

Lynch CM ，Hara PS ，Leonard JC ，Williams JK ，Dean RH ，Geary RL ... -  《CIRCULATION RESEARCH》

Efficient and selective AAV2-mediated gene transfer directed to human vascular endothelial cells.

Nicklin SA ，Buening H ，Dishart KL ，de Alwis M ，Girod A ，Hacker U ，Thrasher AJ ，Ali RR ，Hallek M ，Baker AH ... -  《MOLECULAR THERAPY》