Molecular and Cellular Characterization of AAV1 Vector

AAV1 载体的分子和细胞表征

• 批准号: 6684156
• 负责人: WEIDONG XIAO
• 金额: $ 34万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684156
• 关键词: adeno associated virus group; biotechnology; disease /disorder model; gene delivery system; gene therapy; genetic strain; hemophilia B; laboratory mouse; neutralizing antibody; nonhuman therapy evaluation; transfection /expression vector; virus genetics; virus receptors

Adeno-associated virus (AAV) has been studied extensively as a gene therapy vector. Results from both preclinical studies and clinical trials using recombinant AAV (rAAV) vector suggest that this vector would be safe and effective for muscle gene delivery. Currently, the most widely used rAAV vector is based on AAV serotype 2 because it is the most extensively characterized serotype. Recently, characterization of AAV serotype 1 demonstrated that AAV1 based vectors are approximately 10 to 20-fold more effective than AAV2 for delivery into muscle. Such dramatic differences suggest that AAV1 vector is not merely an alternative vector for AAV2 but has distinctive advantages over the AAV2 vector. Scientifically, AAV1 offers an excellent tool to study the biology and vectorology of AAV. As a continuation of my previous work, the following studies are proposed to characterize AAV1 as a gene therapy vector using hemophilia B as a disease model. 1). To identify the tissue tropism determinants of AAV1 for muscle. The hypothesis to be tested in this specific aim is that some dissimilar amino acid clusters between AAV1 and AAV2 account for the differences in affinity for muscle. Such dramatic differences in transducing muscle provide a reliable assay for the tissue tropism determinants. 2). To characterize the biological properties of AAV1/2 hybrid helpers, and to identify the cellular receptors for AAV1 virus. 3). To explore the effectiveness of AAV 1 and its hybrid derivative vectors in correcting the phenotype in hemophilic mice, and to administer these vectors to animals with neutralizing antibodies against AAV.

腺相关病毒（AAV）作为基因治疗载体已被广泛研究。 使用重组 AAV (rAAV) 载体的临床前研究和临床试验结果表明，该载体对于肌肉基因传递是安全有效的。 目前，最广泛使用的 rAAV 载体基于 AAV 血清型 2，因为它是特征最广泛的血清型。 最近，AAV 血清型 1 的表征表明，基于 AAV1 的载体递送至肌肉的效率比 AAV2 大约高 10 至 20 倍。 如此巨大的差异表明，AAV1 载体不仅是 AAV2 的替代载体，而且比 AAV2 载体具有独特的优势。 从科学角度来说，AAV1 为研究 AAV 的生物学和媒介学提供了一个极好的工具。 作为我之前工作的延续，提出以下研究，以使用 B 型血友病作为疾病模型，将 AAV1 描述为基因治疗载体。 1）。确定 AAV1 对肌肉的组织向性决定因素。 在这个特定目标中要测试的假设是，AAV1 和 AAV2 之间的一些不同的氨基酸簇导致了对肌肉的亲和力差异。 转导肌肉中的这种巨大差异为组织向性决定因素提供了可靠的测定。 2）。表征 AAV1/2 混合辅助病毒的生物学特性，并鉴定 AAV1 病毒的细胞受体。 3）。探讨 AAV 1 及其杂合衍生载体在纠正血友病小鼠表型方面的有效性，并将这些载体施用给具有 AAV 中和抗体的动物。