Binley, K; Askham, Z; Iqball, S; Spearman, H; Martin, L; de Alwis, M; ... Naylor, S; + view all Binley, K; Askham, Z; Iqball, S; Spearman, H; Martin, L; de Alwis, M; Thrasher, AJ; Ali, RR; Maxwell, PH; Kingsman, S; Naylor, S; - view fewer (2002) Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy. BLOOD , 100 (7) 2406 - 2413. 10.1182/blood-2002-02-0605.
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Anemia Is a common clinical problem, and there is much interest In Its role In promoting left ventricular hypertrophy through increasing cardiac workload. Normally, red blood cell production is adjusted through the regulation of erythropoletin (Epo) production by the kidney. One Important cause of anemia Is relative deficiency of Epo, which occurs in most types of renal disease. Clinically, this can be corrected by supplementation with recombinant Epic. Here we describe an oxygen-regulated gene therapy approach to treating homozygous erythropoletin-SV40 T antigen (Epo-TAgh) mice with relative erythropoletin deficiency. We used vectors in which murine Epo expression was directed by an Oxford Blomedica hypoxia response element (OBHRE) or a constitutive cytomegalovirus (CMV) promoter. Both corrected anemia, but CMV-Epo-treated mice acquired fatal polycythemia. In contrast, OBHRE-Epo corrected the hematocrit level in anemic mice to a normal physiologic level that stabilized without resulting In polycythemia. Importantly, the OBHRE-Epo vector had no significant effect on the hematocrit of control mice. Homozygous Epo-TAgh mice display cardiac hypertrophy, a common adaptive response In patients with chronic anemia. In the OBHRE-Epo-treated Epo-TAgh mice, we observed a significant reversal of cardiac hypertrophy. We conclude that the OBHRE promoter gives rise to physiologically regulated Epo secretion such that the hematocrit level is corrected to healthy In anemic Epo-TAgh mice. This establishes that a hypoxia regulatory mechanism similar to the natural mechanism can be achieved, and it makes EPO gene therapy more attractive and safer in clinical settings. We envisage that this control system will allow regulated delivery of therapeutic gene products in other Ischemic settings. (C) 2002 by The American Society of Hematology.
|Title:||Long-term reversal of chronic anemia using a hypoxia-regulated erythropoietin gene therapy|
|Keywords:||IN-VIVO, RENAL-FAILURE, INTRAMUSCULAR INJECTION, ISCHEMIC DISEASE, BETA-THALASSEMIA, TRANSGENIC MICE, CELLS, DELIVERY, VECTORS, DOXYCYCLINE|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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