Hypoxia-modulation of EPO pDNA in Electroporated Muscle

描述（由申请人提供）：使用lchor创新和专有的TriGrid电穿孔系统，在体内肌肉内递送编码促红细胞生成素（EPO）的质粒DNA，在啮齿动物、兔子和灵长类动物中产生了强大的EPO组成表达。虽然高EPO水平对对EPO反应迟钝的患者是有益的，但对于对EPO快速升高敏感的慢性肾衰竭患者，这种高表达并不合适。因此，开发一种生理调节的促生成素基因疗法，在患者贫血和肌注促生成素转基因之间建立更直接的联系，将有利于后一种患者群体。监测红细胞压积和滴定蛋白质剂量的必要性将被消除。毒性可能会降低。最后，非患者的虐待也不太可能发生。

DESCRIPTION (provided by applicant): In vivo intramuscular delivery of plasmid DNA encoding erythropoietin (EPO) using lchor's innovative and proprietary TriGrid electroporation system has resulted in robust constitutive expression of EPO in rodents, rabbits and primates. While high EPO levels are beneficial for patients with blunted responses to EPO, such high expression is not appropriate for chronic renal failure patients who are sensitive to rapid increases in EPO. Development of a physiologically modulated EPO gene therapy with a more direct communication between a patient's anemia and the intramuscularly delivered EPO transgene would thus be of benefit for this latter patient population. The necessities of monitoring hematocrit and titrating doses of the protein would be eliminated. Toxicities could potentially be decreased. Finally, abuse by non-patients would be unlikely. Ichor has demonstrated the feasibility of utilizing anemia-related hypoxia to modulate gene expression from hypoxia-responsive plasmids transfected into anemic mouse muscle. However, this approach must be more thoroughly investigated in a more clinically relevant animal model. Experiments will be performed using rats and will include in vivo screening of HRE-containing plasmids in anemic animals, evaluation of the effect of hypoxia induced by exercise on gene expression, and assessment of hypoxia-modulated EPO transgene expression in a disease model.