Autoimmune anemia in macaques following erythropoietin gene therapy

Blood. 2004 May 1;103(9):3303-4. doi: 10.1182/blood-2003-11-3845. Epub 2004 Jan 22.


We delivered the homologous erythropoietin (Epo) cDNA driven from a doxycycline-regulated promoter via recombinant adeno-associated virus in skeletal muscle of 9 cynomolgus macaques. Upon induction, rapid supraphysiologic levels of Epo were obtained. Unexpectedly, some individuals developed a profound anemia that correlated with the appearance of neutralizing antibodies against the endogenous Epo. Both the endogenous erythropoietin and vector sequences were identical. This is the first example of the inadvertent development of an autoimmune disease in primates as a result of gene transfer of a gene expressing a self-antigen. It raises some concerns when a therapeutic protein is produced at high levels from an ectopic site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Hemolytic, Autoimmune / chemically induced*
  • Animals
  • Autoantibodies / blood
  • Autoimmunity
  • Dependovirus / genetics
  • Doxycycline / pharmacology
  • Drug Evaluation, Preclinical
  • Erythropoietin / administration & dosage*
  • Erythropoietin / adverse effects*
  • Erythropoietin / immunology
  • Genetic Therapy / adverse effects*
  • Genetic Therapy / methods
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / adverse effects
  • Macaca
  • Promoter Regions, Genetic / drug effects


  • Autoantibodies
  • Erythropoietin
  • Doxycycline