Exogenous control of cardiac gene therapy: Evidence of regulated myocardial transgene expression after adenovirus and adeno-associated virus transferof expression cassettes containing corticosteroid response element promoters

Objective: Because of the relative inaccessibility of the heart for repeate d gene therapy, it would be useful to regulate the expression of transgenes delivered in a single dose of a gene therapy vector, Incorporation into th e vector of a regulatable promoter that is responsive to pharmacologic agen ts 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 glucoco rticoid 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 w ith or without dexamethasone. For comparison, rats received a control adeno virus vector, AdCMV.mTPO or AdCMV.Null, and the control adeno-associated vi rus vector AAVCMV.luc, which encodes for the firefly luciferase (luc) gene, Results: Platelet elevation in the AdGRE.mTPO group peaked 4 days after de xamethasone administration, with a return to baseline 1 week after the init ial corticosteroid dose. Subsequent dexamethasone administration at 2 and 4 weeks resulted in similar but progressively decreased responses. The AAVGR E.mTPO group had 5 peak platelet levels to a minimum of 2.2-fold with respe ct to baseline without diminution with subsequent dexamethasone administrat ions out to 169 days. In contrast, the AdCMV.Null and AAVCMV.luc groups dem onstrated no increase in platelet counts and the AdCMV.mTPO group demonstra ted a slow rise to a single peak platelet count independent of dexamethason e administration. Conclusion: It may be possible to control on demand the e xpression of a gene transferred to the heart. This strategy should be usefu l in cardiac gene therapy.