Novel Vector Platform for Gene Therapy

摘要 遗传性血清缺乏性疾病，如血友病和α1-抗胰蛋白酶(AAT)缺乏，已被 被认为是矫正基因治疗的理想候选者。在这方面，病毒载体介导的转导 肝脏已经被提出用于治疗许多这样的疾病，其中肝细胞代表正常的生理 缺乏血清因子的来源。具体地说，基于腺相关病毒(AAV)的载体具有 在动物模型中证明了血友病的有效性，这种方法目前正在被翻译到上下文中 人类临床试验的结果。尽管有这些发现，但一些考虑导致了人们认识到 可能需要替代的矢量方法。首先，与媒介有关的肝脏毒性使 考虑非肝脏来源的血清因子是可取的。另外，对于一些遗传缺陷， AAT缺乏等疾病，AAV介导的体内肝脏转导还没有达到足够的效果 缺乏血清因子水平，以实现有效的基因治疗。我们建议在这里测试我们高度原创的 一种典型血清缺乏症--AAT缺乏性肺的遗传矫正方法 疾病。我们的技术平台显然将产生广泛的领域影响。在第一方面，我们提供技术上的 为全面治疗遗传性血清缺乏症的新的翻译方法奠定了基础。在第二个 考虑到这一点，我们将把Ad设计成一种能够长期表达基因的载体。这种根本性的变化 重要矢量的功能将极大地扩展其可使用的实用程序范围。

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.