Periadventitial lacZ gene transfer to pig carotid arteries using a biodegradable collagen collar or a wrap of collagen sheet with adenoviruses and plasmid-liposome complexes

Abstract

Background Periadventitial gene therapy is a promising alternative for the treatment of stenosis, vessel wall thickening and other complications in vascular surgery. Methods We compared lacZ gene transfer efficiency of DOTMA: DOPE (1:1 w/w) plasmid/liposome complexes and adenoviruses in pig carotid arteries using perivascular delivery with either a collagen collar or a wrap of collagen sheet. Safety of the gene transfer was studied by clinical chemistry, tissue pathology and PCR analysis of lung, liver, kidney, spleen, skeletal muscle and gonads. Results Gene transfer efficiency using the periadventitial collar was fourfold higher than using the collagen wrap with adenovirus at 7 days (10.22 +/- 2.96 vs 2.78 +/- 1.28 positive cells/mm2; p = 0.18) and 4.3-fold at 14 days (13.46 +/- 3.49 vs 3.11 +/- 0.88 positive cells/mm2; p = 0.03). Gene transfer efficiency at 7 days with adenovirus was fivefold higher than with the plasmid/liposome complexes both using the collar (10.22 +/- 2.96 vs 2.07 +/- 0.95 positive cells/mm2; p = 0.01) and the collagen wrap (2.78 +/- 1.28 vs 0.45 +/- 0.35 positive cells/mm2; p = 0.03). No lacZ activity was detected in plasmid/liposome transfected arteries at 14 days. In spite of the local gene delivery methods a moderate systemic distribution of the transgene was detected in the major organs by PCR analysis. Conclusions This study shows that: (i) adenovirus delivered with the periadventitial collar or the collagen wrap is well tolerated and may become an efficient new tool in vascular gene therapy, and (ii) gene transfer vector delivered in the periadventitial collar reaches the target tissue more efficiently than the vector in the collagen wrap.