LONG-TERM ERYTHROPOIETIN EXPRESSION IN RODENTS AND NONHUMAN-PRIMATES FOLLOWING INTRAMUSCULAR INJECTION OF A REPLICATION-DEFECTIVE ADENOVIRAL VECTOR

Erythropoietin (Epo)-responsive anemia is a debilitating complication of chronic renal failure and human immunodeficiency virus (HIV) infect ion that effects more than 150,000 Americans, Patients with Epo-respon sive anemias are currently treated with repeated injections of recombi nant human Epo, In the studies described in this report, we have exami ned the safety and efficacy of using a single intramuscular (i.m.) inj ection of replication-defective adenoviral vectors (RDAd) encoding Epo for the treatment of Epo-responsive anemias in both mice and non-huma n primates, Our results demonstrate that there is a threshold dose of virus (2.5-8 x 10(7) pfu/gram of body weight) which is required to obt ain long-term Epo expression and polycythemia in both species, A singl e i.m. injection of mice with 10(9) pfu of an RDAd encoding murine Epo (AdmEpo) resulted in elevations in hematocrits from control values of 49 +/- 0.9% to treated values of 81 +/- 3%, which were stable for mor e than 1 year, Similarly, a single i.m. injection of a monkey with 4 x 10(11) pfu of an RDAd-encoding simian Epo (AdsEpo) resulted in elevat ions of hematocrits from control levels of 40% to treated levels of gr eater than or equal to 70%, which were stable for 84 days, Intramuscul ar injection of monkeys with AdsEpo appeared to be safe in that we did not detect abnormalities in chest X-rays, serum chemistries, hematolo gic, or clotting profiles (apart from elevated hematocrits) or organ h istologies during the 84-day time course of the experiment, Taken toge ther, these results suggest the feasibility of using i.m. injection of RDAd for the treatment of Epo-responsive anemias in humans.