Background-The muscular dystrophies exemplify a class of systemic disorders for which widespread protein replacement in situ is essential for treatment of the underlying genetic disorder. Somatic gene therapy will require efficient, scale-independent transport of DNA-containing macromolecular complexes too large to cross the continuous endothelia under physiological conditions. Previous studies in large-animal models have revealed a trade-off between the efficiency of gene transfer and the inherent safety of the required surgical and pharmacological interventions to achieve this. Methods and Results-Rats and dogs underwent limb or hemibody isolation via atraumatic tourniquet placement or myocardial isolation via heterotopic transplantation. Recombinant adenovirus (10 13 particles per kilogram) or recombinant adeno-associated virus (10 14 genome copies/kg) encoding the lacZ transgene was delivered through pressurized venous infusion without pharmacological mediators. Muscle exhibited almost 100% myofiber transduction in rats and dogs by X-galactosidase staining and significantly higher ␤-galactosidase levels compared with nonpressurized delivery. No significant difference was seen in ␤-galactosidase levels between 100-or 400-mm Hg groups. The Ͻ50-mm Hg group yielded inhomogeneous and significantly lower transgene expression. Conclusions-Uniform scale-and vector-independent skeletal and cardiac myofiber transduction is facilitated by pressurized venous infusion in anatomic domains isolated from the central circulation without pharmacological interference with cardiovascular homeostasis. We provide the first demonstration of uniform gene transfer to muscle fibers of an entire extremity in the dog, providing a firm foundation for further translational studies of efficacy in canine models for human diseases.

A novel cardiac surgical technique has been developed. This approach with cardiac isolation and retrograde delivery of vector through the coronary sinus results in efficient myocyte transduction in an adult large animal in vivo.

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The lipid coating introduced directly on (polystyrene sulfonate/polyallylamine hydrochloride)5 polyelectrolyte microcapsule surfaces significantly reduces the permeability of capsule walls estimated by fluorescence recovery after photobleaching (FRAP).

There is increased oxidative stress in vitiligo as is indicated by high levels of SOD and low levels of CAT in the skin of vitiligo patients.

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