Improving the Safety Profile of Lentiviral Vectors

描述（由申请人提供）：尽管在过去十年中有大量的临床前动物研究证明了基因治疗的安全性，但Cavazzana-Calvo、Fischer及其同事最近用基因治疗SCID-X1儿童的临床经验表明，采用现有技术的逆转录病毒和慢病毒载体介导的基因治疗可能对患者存在重大风险。虽然对于利用现有技术继续进行临床基因治疗研究的适当性可能存在一些意见分歧，但大多数人都同意，开发安全性更高的载体将大大加快基于逆转录病毒和慢病毒载体的基因治疗的临床开发。拟议的研究计划将集中在慢病毒载体开发的三个技术领域，我们认为这可能对载体的安全性有最大的影响。这些领域包括开发更好和更安全的方法来生产适合临床使用的慢病毒载体，开发更有效的方法来有条件地消除转导细胞，以及开发方法来尽量减少慢病毒介导的基因转移对细胞基因表达的影响。总的来说，这些研究应该会产生有价值的信息、技术和试剂，这些信息、技术和试剂应该会引起基因治疗领域研究人员的广泛兴趣，并且应该会极大地加速重建基于慢病毒载体的基因治疗策略的强大临床开发工作。

DESCRIPTION (provided by applicant): Despite a wealth of pre-clinical animal studies over the past decade which had demonstrated the safety of gene therapy, the recent clinical experience of Cavazzana-Calvo, Fischer and co-workers with the treatment of children with SCID-X1 by gene therapy suggests that retroviral and lentiviral vector mediated gene therapies that employ existing technology may present a significant risk to patients. While there may be some difference in opinion with regard to the appropriateness of continuing clinical gene therapy studies that make use of existing technology, most would agree that the development of vectors with an improved safety profile would significantly accelerate the advancement of the clinical development of retroviral and lentiviral vector-based gene therapies. The proposed research program will focus on three technological areas of lentiviral vector development which we believe could have the most impact on safety profile of the vectors. These areas include the development of better and safer methods to produce lentiviral vectors suitable for clinical use, the development of more effective means to conditionally eliminate transduced cells and the development of methods to minimize the effects of lentiviral-mediated gene transfer on cellular gene expression. Overall, these studies should lead to the generation of valuable information, technology, and reagents that should be of broad interest to investigators working in the field of gene therapy, and should greatly accelerate the re-establishment of a strong clinical development effort in lentiviral vector-based gene therapy strategies.