Molecular Evolution of Retroviral Vectors for Enhanced Gene Delivery

0629202Schaffer本提案是主动提交的。这项研究的目标是应用定向进化和多样性方法来解决基因传递中的两个主要问题：(1)定向传递到特定细胞，在这种情况下是CD34+造血干细胞；(2)定向病毒整合到人类基因组的特定位置。这些结果将提高治疗性基因传递的有效性和安全性，并对病毒感染的机制产生基本的见解。定向进化模拟了自然进化的过程，在这个过程中，产生了大量不同的变种或突变体，并筛选出所需的特性。由于它探索了一个问题的大量可能的解决方案，即使在缺乏合理预测和设计能够成功实现特定目标的变体所需的详细机械知识的情况下，它也被证明是有效的。重要的是，对成功的变种的检验可以极大地提高对机制的理解，并为通过合理的设计进一步完善提供了可能性。

0629202SchafferThis proposal is an unsolicited submission. The goal of the research is to apply directed evolution and diversity approaches to address two major problems in gene delivery: (1) targeting delivery to specific cells, in this case CD34+ hematopoietic stem cells, and (2) targeted viral integration into specific loci of the human genome. The results will enhance the efficacy and safety of therapeutic gene delivery as well as yield fundamental insights into mechanisms of viral infection. Directed evolution emulates the process of natural evolution, in which large numbers of diverse variants, or mutants, are generated and screened for desired properties. Since it explores a vast number of possible solutions to a problem, it proves effective even in the absence of the detailed mechanistic knowledge necessary to rationally predict and design variants that can successfully achieve a specific goal. Importantly, the examination of the resulting successful variants can greatly enhance understanding of mechanism and open the possibility of further refinement by rational design.