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Molecular intervention using noninvasive myocardial gene transfer holds great promise for treating heart diseases. Robust cardiac transduction from peripheral vein injection has been achieved in rodents using adeno-associated virus (AAV) serotype-9 (AAV-9). However, a similar approach has failed to transduce the heart in dogs, a commonly used large animal model for heart diseases. To develop an effective noninvasive method to deliver exogenous genes to the dog heart, we employed an AAV-8 vector that expresses human placental alkaline phosphatase reporter gene under the transcriptional regulation of the Rous sarcoma virus promoter. Vectors were delivered to three neonatal dogs at the doses of 1.35×10(14), 7.14×10(14), and 9.06×10(14) viral genome particles/kg body weight via the jugular vein. Transduction efficiency and overall safety were evaluated at 1.5, 2.5, and 12 months postinjection. AAV delivery was well tolerated and dog growth was normal. Blood chemistry and internal organ histology were unremarkable. Widespread skeletal muscle transduction was observed in all dogs without T-cell infiltration. Encouragingly, whole heart myocardial transduction was achieved in two dogs that received higher doses and cardiac expression lasted for at least 1 year. In summary, peripheral vein AAV-8 injection may represent a simple heart gene transfer method in large mammals. Further optimization of this gene delivery strategy may open the door for a readily applicable gene therapy method to treat many heart diseases.

Long-Term Robust Myocardial Transduction of the Dog Heart from a Peripheral Vein by Adeno-Associated Virus Serotype-8