Nature Medicine
5, 176 - 182 (1999)
doi:10.1038/5538
Gene transfer in utero biologically engineers a patent ductus
arteriosus in lambs by arresting fibronectin−dependent neointimal formationCatherine A. E. Mason1, Jean-Luc Bigras1, 2, Stacy B. O'Blenes1, Bin Zhou1, Brendan McIntyre1, Norimasa Nakamura3, Yasufumi Kaneda3
& Marlene Rabinovitch1
Division of Cardiovascular Research, Research Institute,
The Hospital for Sick Children, Departments of Pediatrics, Laboratory Medicine
and Pathobiology, and Medicine, University of Toronto, 555 University
Avenue, Toronto, Ontario, Canada
M5G 1X8
2
Currently at Hopital Sainte−Justine, Service
de Cardiologie,3175 Ch. Cote−Ste−Catherine, Montreal, Canada H3T 1C5
3
Institute for Molecular and Cellular Biology, Osaka University, 1−3 Yamadagaoka, Suita,Osaka 565, Japan
Correspondence should be addressed to Marlene Rabinovitch Closure of the ductus arteriosus requires prenatal formation of intimal
cushions, which occlude the vessel lumen at birth. Survival of newborns with
severe congenital heart defects, however, depends on ductal patency. We used
a gene transfer approach to create a patent ductus arteriosus by targeting
the fibronectin−dependent smooth muscle cell migration required for
intimal cushion formation. Fetal lamb ductus arteriosus was transfected in utero with hemagglutinating virus of Japan liposomes containing plasmid
encoding 'decoy' RNA to sequester the fibronectin mRNA binding protein. Fibronectin
translation was inhibited and intimal cushion formation was prevented. We
thus established the essential role of fibronectin−dependent smooth
muscle cell migration in intimal cushion formation in the intact animal and
the feasibility of incorporating biological engineering in the management
of congenital heart disease.
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