Autoimmune anemia in macaques following erythropoietin gene therapy.
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.
Chenuaud
Pierre
P
Institut National de la Santé et de la Recherche Médicale, Nantes, France.
Larcher
Thibaut
T
Rabinowitz
Joseph E
JE
Provost
Nathalie
N
Cherel
Yan
Y
Casadevall
Nicole
N
Samulski
Richard J
RJ
Moullier
Philippe
P
D000744:Anemia, Hemolytic, Autoimmune / Q000139:chemically induced*; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity; D000229:Dependovirus / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004921:Erythropoietin / Q000008:administration & dosage* / Q000009:adverse effects* / Q000276:immunology; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D008251:Macaca; D011401:Promoter Regions, Genetic / Q000187:drug effects
D001323:Autoantibodies; D004921:Erythropoietin; D004318:Doxycycline