PHILADELPHIA—If current genetic research in animals proves equally effective in humans, the lungs may someday be used as “metabolic factories” to deliver therapeutic proteins into the bloodstream. A recent study in mice employed adeno-associated virus (AAV) genomes as vectors in the lung to achieve therapeutic blood levels of factor IX and erythropoietin.[1]

“[In the past], the traditional models of lung-directed gene therapy have focused on lung diseases,” said James M. Wilson, MD, PhD, Director of the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia. “We speculated that an airway epithelial cell engineered to express a secreted protein would result in systemic delivery of the protein, which would broaden the scope of diseases amenable to this type of therapy.”

Dr. Wilson and colleagues produced three recombinant AAVs: AAV2, AAV2/5, and AAV2/1, which encoded erythropoietin or factor IX and delivered them into the lungs of mice.

AAV2/5 proved the most promising for use in future gene therapies that target intrapulmonary epithelial cells. When mice were given intranasal AAV2/5 encoding factor IX, serum levels of that coagulation factor increased to 107 ng/mL during the next 45 days and remained elevated for at least 288 days. No factor IX was detected in a control group. The recombinant protein was functional—the activated partial thromboplastin time was markedly reduced in the mice given intranasal AAV2/5. However, the amount necessary to achieve therapeutic levels in humans has yet to be determined.

AAV2/5 also successfully delivered erythropoietin into the systemic circulation. Both serum erythropoietin levels and hematocrits rose significantly in the treated mice, although values declined slowly during the 150 days following administration.

Dr. Wilson said that virtually any disease treatable with systemic delivery of a therapeutic protein would be a candidate for therapy via the lungs. “One key hurdle [in realizing] this potential,” he observed, “is to develop methods to regulate the expression of the gene so the amount of delivered protein is appropriate for the patient’s needs.”

AAV2/5 was also successfully readministered in previously treated mice. Repeated administration of therapy would be essential in the management of chronic diseases.

John F. Engelhardt, PhD, said in a commentary that the study’s most interesting finding was the high efficiency with which erythropoietin and factor IX were secreted from the airway epithelium into circulation—with measurable effects.[2] Professor Engelhardt speculated that “an obvious extension of the work” would be research into whether the lungs could also be used as a “catabolic factory” to degrade products in the circulation that are associated with genetic disease.

Dr. Wilson said that a number of steps—including an extensive safety evaluation—must be taken before this delivery method can be applied in a clinical setting. He and his colleagues are currently evaluating a strategy for its use in nonhuman primates.

—Gale Jurasek