Efficient adenoviral-mediated murine neonatal small intestinal gene transfer is dependent on alpha(v) integrin expression.
OBJECTIVE
Clinical application of gene therapy for patients who have inflammatory bowel disease or short bowel syndrome will require the development of new strategies to improve the efficiency of small intestinal gene transfer. Previously, the authors developed a method for adenoviral-mediated small intestinal gene transfer in vivo in neonatal and adult mice. The present study evaluates the hypothesis that the integrins alpha(v)beta3 and alpha(v)beta5, the secondary receptors for adenoviral internalization, play a facilitative role in neonatal murine adenoviral-mediated small intestinal gene transfer.


METHODS
Immunohistochemical techniques identified the integrin alpha(v)beta3 and the integrin subcomponents alpha(v), beta3, and beta5 in neonatal and adult small intestine. The effects of integrin receptor antagonists on transgene expression was also studied in our neonatal model of adenoviral-mediated small intestinal gene transfer in vivo.


RESULTS
Gene transfer was significantly decreased by the addition of integrin receptor antagonists versus control peptide. Integrin alpha(v)beta3 and integrin subcomponent alpha(v), beta3, and beta5 are expressed in neonatal and adult small intestine. Integrin antagonists administered simultaneously blocked efficient adenoviral-mediated neonatal small intestinal gene transfer in vivo compared with control peptide.


CONCLUSIONS
Strategies to upregulate integrin expression may improve adenoviral-mediated small intestinal gene transfer.
Hamilton
T E
TE
Harrison Department of Surgical Research and Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
McClane
S J
SJ
Baldwin
S
S
Burke
C
C
Patel
H
H
Rombeau
J L
JL
Raper
S E
SE
D000260:Adenoviruses, Human; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D039564:Integrin alphaV; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D019076:Transgenes; D015854:Up-Regulation
D015703:Antigens, CD; D039564:Integrin alphaV; D016023:Integrins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5