Gradient of RGD-dependent entry of adenoviral vector in nasal and intrapulmonary epithelia: implications for gene therapy of cystic fibrosis.
The efficiency with which adenoviral vectors infect airway epithelial cells in vivo is unclear despite extensive preclinical and clinical studies. Our hypothesis is that gene transfer is limited by vector internalization which is mediated by binding of a fiber with a cellular receptor and the RGD motif of the penton base of the virus with cellular alpha v beta integrin. Experiments in mice demonstrate an anatomical gradient of susceptibility to adenoviral vector-mediated gene transfer with epithelia of proximal structures, such as nose and trachea, much less infectable than the distal noncartilaginous airway. Throughout the airway, gene transfer is dependent on RGD-mediated interactions which are rate limiting in the distal lung. A panel of tissues from cystic fibrosis and non-cystic fibrosis patients was analyzed for expression of alpha v beta 5 integrin which is capable of mediating RGD-dependent uptake of vector. Luminal epithelial cells of the nose and trachea were void of alpha v beta 5 expression whereas abundant expression of this integrin was present in virtually all epithelial cells of distal conducting airway. These findings could explain difficulties we and others have had in correcting the functional deficit of cystic fibrosis nasal epithelia and suggest that gene transfer efficiency may be greater in distal human lung.
Goldman
M
M
Department of Medicine, University of Pennsylvania, Philadelphia, USA.
Su
Q
Q
Wilson
J M
JM
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000628:therapy; D004848:Epithelium / Q000821:virology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D039564:Integrin alphaV; D039641:Integrin beta Chains; D016023:Integrins / Q000032:analysis; D008168:Lung / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000378:metabolism / Q000821:virology*; D009842:Oligopeptides / Q000494:pharmacology*; D014132:Trachea / Q000378:metabolism / Q000821:virology
D015703:Antigens, CD; D039564:Integrin alphaV; D039641:Integrin beta Chains; D016023:Integrins; D009842:Oligopeptides; C084344:integrin beta5; C047981:arginyl-glycyl-aspartic acid