LONG-TERM GENE-TRANSFER IN PORCINE MYOCARDIUM AFTER CORONARY INFUSIONOF AN ADENOASSOCIATED VIRUS VECTOR

Background. Viral vector-mediated gene transfer into the heart represe nts a potentially powerful tool for studying both cardiac physiology a s well as gene therapy of cardiac disease. We report here the use of a defective viral vector, which expresses no viral gene products, for g ene transfer into the mammalian heart. Previous studies have used reco mbinant viral vectors, which retained viral genes and yielded mostly s hort-term expression, often with significant inflammation. Methods. An adeno-associated virus vector was used that contains no viral genes a nd is completely free of contaminating helper viruses. The adeno-assoc iated virus vector was applied to rat hearts by direct intramuscular i njection; adeno-associated virus was also infused into pig hearts in v ivo via percutaneous intraarterial infusion into the coronary vasculat ure using routine catheterization techniques. Results. Gene transfer i nto rat heart yielded no apparent inflammation and expression was obse rved for at least 2 months after injection. Infusion into pig circumfl ex coronary arteries resulted in successful transfer and expression of the reporter gene in cardiac myocytes without apparent toxicity or in flammation; gene expression was observed for at least 6 months after i nfusion. Conclusions. We report the use of adeno-associated virus vect ors in the cardiovascular system as well as successful myocardial gene transfer after percutaneous coronary artery infusion of viral vectors in a large, clinically relevant mammalian model. These results sugges t that safe and stable gene transfer can be achieved in the heart usin g standard outpatient cardiac catheterization techniques.