GENE-THERAPY FOR LONG-TERM EXPRESSION OF ERYTHROPOIETIN IN RATS

The injection of recombinant erythropoietin (Epo) is now widely used f or long-term treatment of anemia associated with chronic renal failure , cancer, and human immunodeficiency virus infections. The ability to deliver this hormone by gene therapy rather than by repeated injection s could provide substantial clinical and economic benefits, As a preli minary approach, We investigated in rats the expression and biological effects of transplanting autologous vascular smooth muscle cells tran sduced with a retroviral vector encoding rat Epo cDNA. Vector-derived Epo secretion caused increases in reticulocytes, with peak levels of 7 .8-9.6% around day 10 after implantation, The initial elevation in ret iculocytes was followed by clinically significant increases in hematoc rit and hemoglobin for up to 11 weeks, Ten control and treated animals showed mean hematocrits of 44.9 +/- 0.4% and 58.7 +/- 3.1%, respectiv ely (P < 0.001), and hemoglobin values of 15.6 +/- 0.1 g/dl and 19.8 /- 0.9 g/dl, respectively (P < 0.001). There were no significant diffe rences between control and treated animals in the number of white bloo d cells and platelets: Kidney and to a lesser extent liver are specifi c organs that synthesize Epo in response to tissue oxygenation, In the treated animals, endogenous Epo mRNA was largely down regulated in ki dney and absent from liver, These results indicate that vascular smoot h muscle cells can be genetically modified to provide treatment of ane mias due to Epo deficiency and suggest that this cell type may be targ eted in the treatment of other diseases requiring systemic therapeutic protein delivery,