Long-term erythropoietin expression in rodents and non-human 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) 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 x 10(7) 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 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 more 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 elevations of hematocrits from control levels of 40% to treated levels of > or =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.
Svensson
E C
EC
Department of Medicine, University of Chicago, IL 60637, USA.
Black
H B
HB
Dugger
D L
DL
Tripathy
S K
SK
Goldwasser
E
E
Hao
Z
Z
Chu
L
L
Leiden
J M
JM
D000256:Adenoviridae / Q000235:genetics*; D000740:Anemia / Q000628:therapy*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D003673:Defective Viruses; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D005240:Feasibility Studies; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006400:Hematocrit; D007273:Injections, Intramuscular; D008252:Macaca fascicularis; D051379:Mice; D012377:Rodentia; D013997:Time Factors; D014779:Virus Replication
D000914:Antibodies, Viral; D004921:Erythropoietin