MODIFIED ADENOVIRUS VECTORS FOR THE USE IN GENE THERAPY

基于腺病毒(Ad)的载体已显示出巨大的前景 通过基因疗法来治疗人类的许多疾病。广告向量 有能力在体外将转基因传递给各种类型的细胞 在体内，与基于逆转录病毒的载体不同，Ad载体还可以 有效地转导有丝分裂静止的细胞。因此，潜在的 许多不同的遗传性和非遗传性疾病的治疗可以 可以通过使用广告载体来实现。例如，广告载体 已被证明能够将基因输送到肝脏 用于多种代谢疾病潜在治疗的细胞，2) 肌肉细胞(骨骼和心脏)用于潜在的治疗 肌病和储存障碍，3)脑和神经系统组织 用于帕金森氏症等神经系统疾病的潜在治疗 4)呼吸道上皮细胞用于治疗肺部疾病 像囊性纤维化这样的疾病。此外，许多其他常见疾病 像艾滋病和各种形式的癌症都被证明 有可能通过腺病毒介导的基因转移策略进行治疗。而当 有巨大的潜力来治疗许多人类 疾病，当前的广告载体存在几个问题，必须 在腺病毒介导的基因治疗进入临床之前得到解决 现实。当前广告载体最严重的问题是 转基因成功后的瞬时表达持续时间 进入具有免疫能力的动物的组织中。其他问题 包括第一代可复制广告(RCA)，以及 腺病毒载体无法携带更大的基因。这项拨款建议 概述了一系列实验，这些实验将解决每个 当前广告载体的局限性。在此过程中，我们将隔离修改过的 预测的广告向量允许更长的持续时间 体内转基因表达，降低RCA发生率 生成，并显著增加广告载体的关怀能力。 最初，修改后的Ad载体将在小鼠模型中进行分析 肝脏和肌肉(心脏和骨骼)细胞基因治疗。结果 将分离出能够有效利用的新的Ad载体 人类疾病的动物模型，以及最终用于 治疗人类许多疾病的方法。

Adenovirus (Ad) based vectors have demonstrated great promise for the treatment of many human diseases via gene therapy. 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 o replication competent Ad (RCA), and the inability of Ad vectors to carry larger genes. 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 caring capacity. initially, the modified Ad vectors will be analyzed in mouse models of liver and muscle (cardiac and skeletal) 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.