Local adenovirus-mediated delivery of hirudin in a rabbit arterial injury model

Intravascular delivery of an E1/E3 deleted adenovirus encoding the hirudin protein reduces neointimal formation in the rat arterial injury model. Give n the interspecies variability in response to adenoviral vectors, we tested this same construct in the hirudin-sensitive cholesterol-fed rabbit arteri al balloon injury model. We hypothesized that local delivery of an E1/E3-de leted adenovirus encoding hirudin (Ad-Hir) in addition to early hirudin inf usion would limit neointimal formation compared to early hirudin alone. Met hods and Results: Local delivery of Ad-Hir, 2.5 x 10(10) PFU/ml, using a do uble balloon catheter [n = 6 vessels (v)] produced a 79% reduction in vesse l wall thrombin activity at 48 h after balloon angioplasty (BA) compared wi th vehicle (Veh, n = 6v; p = 0.05). In chronic experiments, hypercholestero lemic rabbits underwent femoral BA, and received either early hirudin alone (n = 9v) or early hirudin plus locally delivered Ad-Hir (early hirudin + A d-Hir; n = 9v), an E1/E3-deleted adenovirus encoding beta-galactosidase (ea rly hirudin + Ad-Gal; n = 7v), or Veh (early hirudin + Veh; n = 10v). Early hirudin + Ad-Hir did not limit the arterial response to injury versus the other groups at 4 weeks after BA. Plaque area, cross-sectional luminal area narrowing by plaque, and T cell infiltration were significantly increased in the adenovirus- versus non-adenovirus-treated arteries. Plaque area corr elated with T cell density. Conclusion: Following BA in cholesterol-fed rab bits, local transduction with A-Hir produced a marked reduction in vessel w all-associated thrombin activity. However, this strategy increased rather t han decreased the arterial response to BA injury. Our results suggest that the lack of therapeutic effect resulted from adenovirus-stimulated plaque f ormation, possibly resulting from a T cell-mediated inflammatory response. Copyright (C) 1999 S. Karger AG, Basel.