A recombinant adenovirus for targeted gene therapy of pulmonary inflammation (155.23)

Abstract

Abstract Inflammation is a pathological component of many debilitating lung diseases. Thus, therapeutics that suppress the inflammatory response should also minimize inflammation-induced airway destruction. In this regard, Adenovirus type 5 (Ad5) vectors have a long history as therapeutic agents, due to their in vivo stability and amenability to genetic manipulation. Since circulating leukocytes infiltrate and mediate damage to the sites of pathology, we proposed to modulate Ad5 tropism to the dense leukocyte pool in the lung microvasculature for localized therapeutic intervention of inflammation. However, leukocytes do not express the coxsackie and adenovirus receptor (CAR) and are thus resistant to Ad5 infection. Therefore, we utilized phage display to identify a myeloid-binding peptide (MBP) and then genetically incorporated this sequence into an Ad5 fiber lacking the native CAR-binding domain (knob). Non-replicative Ad reporter vectors containing these MBP-fibers (Ad.MBP) maintained myeloid-binding specificity, and upon intravenous delivery the altered tropism enhanced lung gene transfer by five orders of magnitude over that obtained with unmodified Ad5. Disparity between cell types bound and those transduced suggest Ad.MBP is first sequestered by circulating leukocytes and subsequently “handed-off” to transduce pulmonary endothelium. These studies highlight the importance of pulmonary leukocytes as a target for therapeutic delivery in inflammatory lung disease.