TY - JOUR
T1 - Stable delivery of physiologic levels of recombinant erythropoietin to the systemic circulation by intramuscular injection of replication-defective adenovirus
AU - Tripathy, Sandeep K.
AU - Goldwasser, Eugene
AU - Lu, Min Min
AU - Barr, Eliav
AU - Leiden, Jeffrey M.
PY - 1994/11/22
Y1 - 1994/11/22
N2 - 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 1α (EF1α) promoter and the 4F2 heavy chain (4F2HC) enhancer. Neonatal CD-1 and adult SCID mice injected once intramuscularly (i.m.) with 107 to 109 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.
AB - 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 1α (EF1α) promoter and the 4F2 heavy chain (4F2HC) enhancer. Neonatal CD-1 and adult SCID mice injected once intramuscularly (i.m.) with 107 to 109 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.
UR - https://www.scopus.com/pages/publications/0028032357
U2 - 10.1073/pnas.91.24.11557
DO - 10.1073/pnas.91.24.11557
M3 - Article
C2 - 7972101
AN - SCOPUS:0028032357
SN - 0027-8424
VL - 91
SP - 11557
EP - 11561
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -