Novel Vector Platform for Gene Therapy

摘要 遗传性血清缺乏症，如血友病和α1-抗胰蛋白酶（AAT）缺乏症， 被认为是矫正基因疗法的理想候选者。在这方面，病毒载体介导的转导的细胞因子的表达是非常重要的。 肝已经被提出用于许多这样的疾病，其中肝细胞代表正常的生理功能。 缺乏血清因子的来源。具体地，基于腺相关病毒（AAV）的载体具有 在血友病动物模型中证明了实用性，这种方法目前正在转化为背景 人体临床试验的结果尽管有这些发现，但一些考虑因素使人们认识到， 可能需要替代的矢量方法。首先，媒介相关的肝脏毒性使 考虑血清因子的非肝来源是可取的。此外，对于某些遗传性缺陷， 在某些疾病中，例如AAT缺乏，AAV介导的肝脏体内转导尚未实现足够的 水平的缺陷血清因子，以实现有效的基因治疗。我们在这里提出测试我们高度原创的 实现原型血清缺乏性疾病- AAT缺乏性肺的遗传校正的方法 疾病我们的技术平台显然将产生广泛的领域影响。首先，我们提供技术支持。 为全系列遗传性血清缺乏症的新翻译方法奠定了基础。在第二 考虑到这一点，我们将设计Ad作为能够长期基因表达的载体。这种根本性的变化 important vector的功能将极大地扩展其应用范围。

ABSTRACT Inherited serum deficiency disorders, such as hemophilia and α1-antitrypsin (AAT) deficiency, have been considered ideal candidates for corrective gene therapy. In this regard, viral vector-mediated transduction of the liver has been proposed for a number of such disorders wherein hepatocytes represent the normal physiologic source of the deficient serum factor. Specifically, adeno-associated virus (AAV)-based vectors have demonstrated utility in hemophilia in animal models and this approach is presently being translated to the context of human clinical trials. Despite these findings, a number of considerations have led to the recognition that alternative vector approaches may be required. In the first instance, vector-related liver toxicities make consideration of non-hepatic sourcing of serum factors desirable. In addition, for some inherited deficiency disorders, such as AAT deficiency, AAV-mediated in vivo transduction of the liver has not achieved adequate levels of the deficient serum factor to achieve effective gene therapy. We propose here to test our highly original approach to accomplish genetic correction of a prototype serum deficiency disorders – AAT deficiency lung disease. Our technology platform will clearly have broad field impact. In the first regard, we provide the technical basis for a new translational approaches for the full range of inherited serum deficiency disorders. In the second regard, we will engineer Ad as a vehicle capable of long term gene expression. This fundamental change in this important vector's functionalities will dramatically expand the range of utilities whereby it can be employed.