Improving the Safety Profile of Lentiviral Vectors

描述（由申请人提供）：尽管过去十年大量的临床前动物研究已经证明了基因治疗的安全性，但 Cavazzana-Calvo、Fischer 及其同事最近通过基因治疗治疗 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会给患者带来重大风险。尽管对于利用现有技术进行持续临床基因治疗研究的适当性可能存在一些不同意见，但大多数人都同意开发具有改进安全性的载体将显着加速基于逆转录病毒和慢病毒载体的基因治疗的临床开发进展。拟议的研究计划将重点关注慢病毒载体开发的三个技术领域，我们认为这对载体的安全性影响最大。这些领域包括开发更好、更安全的方法来生产适合临床使用的慢病毒载体，开发更有效的手段来有条件地消除转导的细胞，以及开发方法来最大限度地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，这些研究应该产生有价值的信息、技术和试剂，这些信息、技术和试剂应该引起基因治疗领域研究人员的广泛兴趣，并且应该大大加速基于慢病毒载体的基因治疗策略的强大临床开发工作的重建。

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.