A Mini-Ad Vector for Treatment of Factor VIII Deficiency

描述(申请人提供)：遗传性凝血障碍 血友病A是由于FVIII的表达或功能缺乏所致。 MiniAdF VIII载体是一种“没有胆量”的腺病毒载体，旨在 将完整的FVIII基因导入体细胞获得人FVIII。 非临床药理学、毒理学和生物分布研究 已执行。重要的是，生理水平的FVIII是在体内产生的， 而这些水平持续了很长一段时间，导致 血友病小鼠和狗的表型校正。 这项临床研究的目的是通过剂量递增来评估 重症甲型血友病患者静脉输注MiniAdFVIII载体的安全性 未使用抑制剂的患者。这项研究的其他目标如下 如下：(1)通过剂量递增评估静脉注射的能力 注射MiniAdFVIlI载体以产生循环的、功能水平的 FVIII，(2)评价MiniAdFVIIl载体疗法对小鼠心脏功能的影响 确定剂量递增后出血事件的频率和严重程度 (3)评价应用MiniAdF后的免疫应答。 通过监测抗腺病毒和抗FVIII抗体效价的方法构建VIII3载体 血，以及(4)通过以下方式确定FVIII的功能性表达谱 测量功能和循环的水平、时间进程和持续时间 Fviii. 建议的商业应用：不可用

DESCRIPTION (provided by applicant): The inherited blood coagulation disorder hemophilia A results from deficiency in the expression or function of FVIII. The MiniAdF VIII vector is a "gutless" adenovirus vector designed to restore production of human FVIII by delivering the entire FVIII cDNA to somatic cells. Nonclinical pharmacology, toxicology and biodistribution studies have been performed. Importantly, physiological levels of FVIII were produced in vivo, and these levels persisted for an extended period of time, resulting in phenotypic correction in hemophilic mice and dogs. The objective of this clinical study is to evaluate through dose escalation the safety of intravenous infusion of MiniAdFVIII vector in severe hemophilia A patients without inhibitors. Additional objectives of this study are as follows: (1) to evaluate through dose escalation the ability of an intravenous infusion of MiniAdFVIlI vector to produce circulating, functional levels of FVIII, (2) to evaluate the effect of MiniAdFVIIl vector therapy on the frequency and severity of bleeding events following defined dose escalation, (3) to evaluate immunologic responses following the administration of MiniAdF VIII vector by monitoring anti-adenoviral and anti-FVIII antibody titers in blood, and (4) to determine the functional FVIII expression profile by measuring the level, time course, and duration of functional and circulating FVIII. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE