Molecular Engineering of AAV for Stealth and Targeting

AAV 的隐形和靶向分子工程

• 批准号: 6736556
• 负责人: DAVID V SCHAFFER
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6736556
• 关键词: adeno associated virus group; biotechnology; cell line; gene delivery system; gene targeting; neutralizing antibody; nucleic acid chemical synthesis; polyethylene glycols; recombinant virus; technology /technique development

DESCRIPTION (provided by applicant): Gene therapy has vast potential for treating and potentially curing a wide variety of disorders. However, gene delivery technologies require significant improvements in safety, efficiency, and expression stability before the majority of these diseases can be treated. Vectors based on adeno-associated virus (AAV) have proven themselves to be highly promising, both in the laboratory and the clinic, but they still suffer from several shortcomings. In particular, they are unable to readily target gene delivery to specific cell types, and their efficiency is compromised by their recognition and neutralization by the immune system. These two liabilities are a result of the surface properties of this virus, and we will implement a combined chemical synthesis and molecular biology approach to engineer the viral surface for targeted gene delivery and enhanced stealth. Specifically, the genetic insertion of a peptide tag into the viral capsid will allow the modular and reversible attachment of chemically synthesized targeting peptides and stealthing polymers. In effect, this already effective product of nature is being engineered to better match human therapeutic needs. The Specific Aims are: 1. To determine whether a combined, modular chemical and genetic approach can effectively target AAV gene delivery 2. To determine whether polyethylene glycol can "stealth" AAV from neutralizing antibodies The novel blend of synthetic chemistry, molecular biology, and bioengineering described in this proposal will be well suited to addressing this problem at the interface of engineering and medicine.

描述（由申请人提供）：基因治疗具有治疗和潜在治疗多种疾病的巨大潜力。 但是，在可以治疗大多数疾病之前，基因递送技术需要显着改善安全性，效率和表达稳定性。 在实验室和诊所中，基于腺相关病毒（AAV）基于腺相关病毒（AAV）的载体已经非常有前途，但它们仍然遭受了几个缺点。 特别是，它们无法轻易地将基因递送到特定的细胞类型中，并且免疫系统的识别和中和损害了它们的效率。 这两个负债是该病毒表面特性的结果，我们将实施一种合并的化学合成和分子生物学方法来设计病毒表面的靶向基因递送和增强的隐形。 具体而言，将肽标签的遗传插入到病毒式衣壳中将允许化学合成的靶向肽和窃取聚合物的模块化和可逆附着。 实际上，这种已经有效的自然产物正在设计中，以更好地匹配人类的治疗需求。 具体目的是：1。确定合并的，模块化的化学和遗传方法是否可以有效地靶向AAV基因递送2。确定聚乙烯乙二醇是否可以从中和中和抗体中“隐身” AAV抗体的新型合成化学，分子生物学和生物工程的新型融合在此建议中所描述的对这一问题的良好型疗法将适合于该问题和工程的问题，并且在工程中均可在互联面上融合。