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(Circulation. 1997;96:3561-3569.)
© 1997 American Heart Association, Inc.

Articles

In Utero Cardiac Gene Transfer via Intraplacental Delivery of Recombinant Adenovirus

Y. Joseph Woo, MD; G. Praveen Raju, BA; Judith L. Swain, MD; Marc E. Richmond; Timothy J. Gardner, MD; ; Rita J. Balice-Gordon, PhD

From the Departments of Surgery (Y.J.W., T.J.G.), Medicine (G.P.R., J.L.S., M.E.R.), and Neuroscience (R.J.B.-G.), University of Pennsylvania School of Medicine (Philadelphia). Dr Swain is now at the Department of Medicine, Stanford University Medical Center, S-102, Stanford, CA 94305-5109.

Correspondence to Rita J. Balice-Gordon, PhD, Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104-6074. E-mail rbaliceg{at}mail.med.upenn.edu

Background The relationship among the maternal, placental, and uniquely shunted embryonic circulation was explored to provide access to the embryonic cardiovascular system in utero. Manipulation of gene expression in the developing heart would be particularly useful for studying the effects of altered gene expression on cardiac development and in the etiology of congenital cardiac anomalies.

Methods and Results Dye studies demonstrated that intraplacental injection allows direct access to the embryonic cardiac and systemic circulation. To evaluate the efficacy of cardiac gene transfer using this approach, replication-deficient recombinant adenoviral vectors encoding luciferase or ß-galactosidase as reporter genes were injected intraplacentally into embryonic day (E)12.5 murine embryos, an age at which the mass of the heart was observed to be large compared with other organs. Embryos were assayed for transgene expression at E15.5 and at birth. Survival rates at these times were similar among vector-injected and control groups. At E15.5 and at birth, luciferase activity within the heart was 9- and 23-fold higher, respectively, than in the remainder of the embryo, although levels of expression were generally lower at birth than during embryonic life. ß-Galactosidase expression was observed within all regions of the embryonic heart and was localized to 15% of atrial and ventricular cells.

Conclusions Intraplacental delivery of adenovirus at embryonic day 12.5 results in somatic gene transfer to the murine embryonic heart, which persists at least until birth. The combination of intraplacental injection to directly access the fetal coronary circulation and injection at E12.5 when the mass of the heart is large compared with other organs results in transgene expression in cardiac cells. Intraplacental injections early in embryonic life may thus be useful to study the effects of temporal manipulation of gene expression on cardiac development and disease.

Key Words: genes • viruses • heart defects, congenital • cardiovascular diseases

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