MODIFIED ADENOVIRUS VECTORS FOR USE IN GENE THERAPY

Ad载体具有将转基因递送至多种细胞的能力， 类型，在体外和体内，并且不同于基于逆转录病毒的载体，Ad 载体也可以有效地抑制静止细胞的分裂。 因此，许多不同疾病的潜在治疗， 遗传的和非遗传的可以通过使用Ad载体来设想。 例如，已经证明Ad载体能够 将基因输送到1）肝细胞，用于治疗许多 代谢紊乱，2）肌肉细胞（骨骼和心脏）， 可能治疗肌病和存储障碍，3）脑和 用于神经系统疾病的潜在治疗的神经系统组织 疾病，如帕金森病，和4）呼吸道上皮细胞， 治疗肺部疾病，如囊性纤维化。 此外，本发明还提供了一种方法， 许多其他常见疾病，如艾滋病和各种癌症， 所有这些都被证明可以通过Ad介导的基因治疗 转移策略。虽然有巨大的潜力， 在治疗许多人类疾病方面， 在Ad介导的基因转移之前必须解决的现有Ad载体 治疗成为临床现实。 最严重的问题 目前的Ad载体是转基因表达的瞬时持续时间 在成功地将基因递送到免疫活性组织中后， 动物 其他问题包括复制能力的产生 Ad（RCA），以及Ad载体不能携带更大的基因或 组织特异性启动子/增强子元件。 这份拨款申请 概述了一系列的实验，将解决每一个 当前广告载体的局限性。 这样一来，我们就可以隔离 被预测为允许更长的广告持续时间的修改的广告向量 体内转基因表达，降低RCA产生的发生率， 显著提高Ad载体的携带能力。 最初 将在小鼠肝脏和肌肉模型中分析修饰的Ad载体 细胞基因疗法 结果将是新的Ad载体的分离 也能够有效地用于人类疾病的动物模型， 至于最终用于治疗大量的人类 条件

Ad vectors have the ability to deliver transgenes to a variety of cell types, in vitro and in vivo, and unlike retrovirus based vectors, Ad vectors can also efficiently transduce mitotically quiescent cells. Therefore, the potential treatment of many different diseases, both genetic and non-genetic can be envisioned with the use of Ad vectors. For example, Ad vectors have been demonstrated to be capable of delivering genes to 1) liver cells for the potential treatment of many metabolic disorders, 2) muscle cells (skeletal and cardiac) for the potential treatment of myopathies and storage disorders, 3) brain and nervous system tissues for the potential treatment of neurologic diseases like Parkinson disease, and 4) respiratory epithelium for the treatment of pulmonary disorders like cystic fibrosis. In addition, many other common diseases like AIDS and various forms of cancer have all been demonstrated to be potentially treated by Ad mediated gene transfer strategies. While there is an enormous potential for the treatment of many human diseases, there are several problems with current Ad vectors that must be addressed before Ad mediated gene therapy becomes a clinical reality. The most serious problem with current Ad vectors is the transient duration of transgene expression after successful gene delivery into the tissues of immunocompetent animals. Other problems include the generation of replication competent Ad (RCA), and the inability of Ad vectors to carry larger genes or tissue-specific promoter/enhancer elements. This grant proposal outlines a series of experiments that will address each of the limitations of current Ad vectors. In so doing, we will isolate modified Ad vectors that are predicted to allow for longer durations of transgene expression in vivo, decrease the incidence of RCA generation, and significantly increase Ad vector carrying capacity. Initially, the modified Ad vectors will be analyzed in mouse models of liver and muscle cell gene therapy. The result will be the isolation of new Ad vectors capable of efficacious use in animal models of human disease, as well as for eventual use in the therapy of a great number of human conditions.