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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Nov 22;91(24):11557–11561. doi: 10.1073/pnas.91.24.11557

Stable delivery of physiologic levels of recombinant erythropoietin to the systemic circulation by intramuscular injection of replication-defective adenovirus.

S K Tripathy 1, E Goldwasser 1, M M Lu 1, E Barr 1, J M Leiden 1
PMCID: PMC45270  PMID: 7972101

Abstract

A number of inherited and acquired serum protein deficiencies including hemophilias A and B, diabetes mellitus, and the erythropoietin-responsive anemias are currently treated with repeated subcutaneous or intravenous infusions of purified or recombinant proteins. The development of an in vivo gene-transfer approach to deliver physiologic levels of recombinant proteins to the systemic circulation would represent a significant advance in the treatment of these disorders. Here we describe the construction of a replication-defective adenovirus (AdEF1hEpo) containing the human erythropoietin (hEpo) cDNA under the transcriptional control of the cellular elongation factor 1 alpha (EF1 alpha) promoter and the 4F2 heavy chain (4F2HC) enhancer. Neonatal CD-1 and adult SCID mice injected once intramuscularly (i.m.) with 10(7) to 10(9) plaque-forming units (pfu) of this virus displayed significant dose-dependent elevations of serum hEpo levels and increased hematocrits, which were stable over the 4-month time course of these experiments. Adenovirus injected i.m. remained localized at the site of injection and there was no evidence of either systemic infection or a localized inflammatory response. These results suggest that i.m. injection of recombinant replication-defective adenovirus vectors may serve as a paradigm for the treatment of human serum protein deficiencies.

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Selected References

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