A gene therapy approach to regulated delivery of erythropoietin as a function of oxygen tension

Hum Gene Ther. 1997 Nov 1;8(16):1881-9. doi: 10.1089/hum.1997.8.16-1881.


Current therapy for several forms of anemia involves a weekly regime of multiple subcutaneous injections of recombinant human erythropoietin (hEpo). In an effort to provide a physiologically regulated administration of erythropoietin, we are developing cell lines genetically engineered to release hEpo as a function of oxygen tension. C2C12 cells were transfected using a vector containing the hEpo cDNA driven by the hypoxia-responsive promoter to the murine phosphoglycerate kinase gene. In vitro, these cells showed a threefold increase in hEpo secretion as oxygen levels were shifted from 21% to 1.3% oxygen. To test in vivo response, C2C12-hEpo cells were encapsulated in a microporous membrane and implanted subcutaneously on the dorsal flank of DBA/2J mice. On average, serum hEpo levels in animals exposed to 7% oxygen were two-fold higher than values seen in their control counterparts kept at 21% oxygen. Similar studies employing rats confirmed that hEpo delivery is regulated as a function of oxygen tension. These results suggest the feasibility of developing an oxygen-regulated, encapsulated cell-based system for hEpo delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / therapy
  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • Drug Compounding
  • Erythropoietin / blood
  • Erythropoietin / genetics*
  • Erythropoietin / metabolism
  • Gene Expression Regulation*
  • Genetic Therapy / methods*
  • Histocytochemistry
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mice
  • Mice, Inbred DBA
  • Nuclear Proteins / genetics
  • Oxygen / blood
  • Oxygen / physiology*
  • Partial Pressure
  • Phosphoglycerate Kinase / genetics
  • Plasmids / genetics
  • Promoter Regions, Genetic / genetics
  • Rats
  • Rats, Inbred F344
  • Recombinant Proteins
  • Transcription Factors*
  • Transgenes*


  • DNA-Binding Proteins
  • Hif1a protein, mouse
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Recombinant Proteins
  • Transcription Factors
  • Erythropoietin
  • Phosphoglycerate Kinase
  • Oxygen