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Long-Term Erythropoietin Expression in Rodents and Non-Human Primates Following Intramuscular Injection of a Replication-Defective Adenoviral Vector

1997; Mary Ann Liebert, Inc.; Volume: 8; Issue: 15 Linguagem: Inglês

10.1089/hum.1997.8.15-1797

1557-7422

E. C. Svensson, Hugh B. Black, Debra L. Dugger, Sandeep K. Tripathy, Eugene Goldwasser, Zengping Hao, Lien Chu, Jeffrey M. Leiden,

CRISPR and Genetic Engineering

Erythropoietin (Epo)-responsive anemia is a debilitating complication of chronic renal failure and human immunodeficiency virus (HIV) infection that effects more than 150,000 Americans. Patients with Epo-responsive anemias are currently treated with repeated injections of recombinant human Epo. In the studies described in this report, we have examined the safety and efficacy of using a single intramuscular (i.m.) injection of replication-defective adenoviral vectors (RDAd) encoding Epo for the treatment of Epo-responsive anemias in both mice and non-human primates. Our results demonstrate that there is a threshold dose of virus (2.5–8 × 107 pfu/gram of body weight) which is required to obtain long-term Epo expression and polycythemia in both species. A single i.m. injection of mice with 109 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 more than 1 year. Similarly, a single i.m. injection of a monkey with 4 × 1011 pfu of an RDAd-encoding simian Epo (AdsEpo) resulted in elevations of hematocrits from control levels of 40% to treated levels of ≥70%, which were stable for 84 days. Intramuscular injection of monkeys with AdsEpo appeared to be safe in that we did not detect abnormalities in chest X-rays, serum chemistries, hematologic, or clotting profiles (apart from elevated hematocrits) or organ histologies during the 84-day time course of the experiment. Taken together, these results suggest the feasibility of using i.m. injection of RDAd for the treatment of Epo-responsive anemias in humans. We have examined the safety and efficacy of using intramuscular (i.m.) injection of E1- and E3-deleted replication defective adenoviruses (RDAd) encoding erythropoietin (Epo) for the treatment of Epo-responsive anemias in both mice and non-human primates. Our results demonstrate that a single injection of adult immunocompetent mice or cynomologous monkeys with 2.5–8.0 × 107 pfu of RDAd/gm body weight results in the expression of physiological levels of erythropoietin in the systemic circulation of both species. Elevated levels of Epo were detected in the serum for at least 1 year following i.m. injection of mice and for at least 84 days following injection of the monkeys. Intramuscular injection of non-human primates with an RdAd-encoding simian Epo appeared to be safe because we did not detect abnormalities in chest X-rays, serum chemistries, hematologic profiles, or organ histologies. These findings suggest that i.m. injection of RDAd may represent an effective therapy for humans with Epo-responsive anemias.