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J Thorac Cardiovasc Surg 1999;118:26-25
© 1999 Mosby, Inc.

SURGERY FOR ACQUIRED CARDIOVASCULAR DISEASE

EXOGENOUS CONTROL OF CARDIAC GENE THERAPY: EVIDENCE OF REGULATED MYOCARDIAL TRANSGENE EXPRESSION AFTER ADENOVIRUS AND ADENO-ASSOCIATED VIRUS TRANSFER OF EXPRESSION CASSETTES CONTAINING CORTICOSTEROID RESPONSE ELEMENT PROMOTERS

From the Division of Pulmonary and Critical Care Medicine^a and Department of Cardiothoracic Surgery,^b The New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, NY.

L.Y.L. and X.Z. contributed equally as principal investigators in this study. R.G.C. and T.K.R. contributed equally as senior investigators in this study.

Address for reprints: The New York Presbyterian Hospital–Weill Medical College of Cornell University, 525 East 68th St, Suite F2103, New York, NY 10021.

Objective: Because of the relative inaccessibility of the heart for repeated gene therapy, it would be useful to regulate the expression of transgenes delivered in a single dose of a gene therapy vector. Incorporation into the vector of a regulatable promoter that is responsive to pharmacologic agents that are widely used and well tolerated in clinical practice represents such a control strategy.
Methods: A replication-deficient adenovirus or an adeno-associated virus containing a chimeric promoter composed of 5 glucocorticoid response elements and the murine thrombopoietin complementary DNA (AdGRE.mTPO or AAVGRE.mTPO) was administered to the hearts of Sprague-Dawley rats. Platelet levels were evaluated as a reporter of transgene activity with or without dexamethasone. For comparison, rats received a control adenovirus vector, AdCMV.mTPO or AdCMV.Null, and the control adeno-associated virus vector AAVCMV.luc, which encodes for the firefly luciferase (luc) gene.
Results: Platelet elevation in the AdGRE.mTPO group peaked 4 days after dexamethasone administration, with a return to baseline 1 week after the initial corticosteroid dose. Subsequent dexamethasone administration at 2 and 4 weeks resulted in similar but progressively decreased responses. The AAVGRE.mTPO group had 5 peak platelet levels to a minimum of 2.2-fold with respect to baseline without diminution with subsequent dexamethasone administrations out to 169 days. In contrast, the AdCMV.Null and AAVCMV.luc groups demonstrated no increase in platelet counts and the AdCMV.mTPO group demonstrated a slow rise to a single peak platelet count independent of dexamethasone administration.
Conclusion: It may be possible to control on demand the expression of a gene transferred to the heart. This strategy should be useful in cardiac gene therapy.

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