Adeno-associated Virus Vectors for Targeted and Repeat Delivery

用于靶向和重复递送的腺相关病毒载体 项目1“用于靶向和重复传递的腺相关病毒载体”将利用AAV 矢量结果来自正在进行的AAV I期DMD临床试验。新型AAV载体的出现 (血清型1-11)和衣壳晶体结构的解决，使我们和其他人能够进行理性 设计AAV衣壳以产生基因输送载体的实验室毒株。使用这种方法，我们 已经成功地将AAV2型嗜肝载体改造成嗜肌病毒，仅用5 来源于AAV 1型衣壳骨架的氨基酸。这种新型嵌合试剂(AAV2.5)具有明显的 与亲本血清型衣壳骨架相比，免疫谱对肌肉有很高的效率 转导。由于这种嵌合AAV颗粒的优势，我们最近启动了一个I期基因 与肖医生一起治疗DMD的临床试验。从这些努力中获得的早期信息提供了 假说驱动的方法，以更好地了解基本步骤，如对病毒衣壳的免疫反应， 病毒/受体相互作用、细胞内转运和转基因表达。在建议的研究中，我们 希望利用这些观察结果，获得一组具有新型免疫功能的致病载体 允许重复管理的配置文件。这些目标将通过AAV DNA的可用性来实现 衣壳文库技术，抗患者中和血清筛选(包括正在进行的AAV临床试验)， 以及使用携带肌肉特定疾病特征的大型动物模型(项目3)。我们的目标是更好地 了解有效的载体肌肉转导的分子机制，这将使这些和其他 用于骨骼和心脏特异性肌肉基因治疗的新型递送试剂。这些研究的成功将 促进项目2的近期目标和启动肌肉临床试验的长期目标 精神错乱。

Adeno-associated Virus Vectors for Targeted and Repeat Delivery Project 1 "Adeno-associated Virus Vectors for Targeted and Repeat Delivery" will capitalize on AAV vector results derived from the on-going AAV Phase I DMD clinical trial. The advent of novel AAV vectors (serotype 1-11) and the solving of the capsid crystal structure, has allowed us and others to carry out rational design of AAV capsids to generate laboratory strains of gene delivery vehicles. Using such an approach, we have been successful in engineering AAV type 2 liver tropic vectors into a muscle tropic virus using only 5 amino acids derived from AAV type 1 capsid backbone. This novel chimeric reagent (AAV 2.5) has a distinct immune profile when compared to capsid backbone of parent serotypes and has high efficiency for muscle transduction. Due to the advantages of this chimeric AAV particle we recently initiated a Phase I Gene Therapy clinical trial for DMD with Dr. Xiao. Early information derived from these efforts has provided hypothesis driven approaches to better understand basic steps such as immune response to viral capsid, viral /receptor interaction, intra-cellular trafficking, and transgene expression. In the proposed studies, we hope to capitalize on these observations by deriving a collection of disease tropic vectors with novel immune profile that will allow for repeat administration. These objectives will be carried out by availability to AAV DNA capsid library technology, selection against patient neutralizing serum (including on-going AAV clinical trial), and use of large animal models carrying muscle specific disease traits (Project 3). Our objective is to better understand the molecular mechanism of efficient vector muscle transduction that will allow these and other novel delivery reagents for skeletal and heart specific muscle gene therapy. Success of these studies will facilitate the immediate goals of Project 2 and the long-term objective of initiating clinical trial for muscle disorders.