Lentiviral Gene Therapy for Wiskott-Aldrich Syndrome

威斯科特-奥尔德里奇综合征的慢病毒基因治疗

• 批准号: 8029506
• 负责人: David J Rawlings
• 金额: $ 71.55万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029506
• 关键词: Address; Adoptive Cell Transfers; Age; Animal Model; Animals; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bacteria; Biological Assay; Blood Platelets; Bone Marrow; Cell Line; Cell Lineage; Cells; Clinical; Clinical Trials; Data; Defect; Development; Disease; Disease Management; Encapsulated; Enhancers; Exhibits; Generations; Genes; Genetic; Goals; HIV; Half-Life; Hematopoietic; Hematopoietic stem cells; Homeostasis; Human; Human Activities; Immunologics; In Vitro; Incidence; Individual; Infection; Kinetics; Knockout Mice; Lead; Lentivirus Vector; Life; Lymphoid; Mediating; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Patients; Peripheral; Platelet Count measurement; Pre-Clinical Model; Predisposition; Proteins; Regulatory T-Lymphocyte; Research; Role; Safety; Site; Streptococcus pneumoniae; System; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translations; Transplantation; Viral; Wiskott-Aldrich Syndrome; Work; base; experience; falls; gene correction; gene delivery system; gene replacement; gene therapy; immune function; in vitro Model; in vivo; knockout animal; nonhuman primate; promoter; research study; success; vector

DESCRIPTION (provided by applicant): This proposal seeks to develop an effective and safe pre-clinical model for gene therapy in Wiskott- Aldrich Syndrome (WAS). While transplantation using HLA-matched bone marrow can be curative for young WAS patients, the success rate falls precipitously with increasing age. Multiple lines of evidence document a strong selective advantage for WASP expressing hematopoeitic cell subsets suggesting that introduction of the normal WASP gene into hematopoietic stem cells (HSC) could provide a viable therapeutic alternative in disease management. While conceptually simple, development of a safe and effective strategy for WASP gene replacement requires extensive pre-clinical modeling in human and animal systems. This proposal takes advantage of combined expertise, and a network of important research and clinical collaborators, to establish a lentiviral delivery system for the definitive genetic treatment of WAS. We will test the hypotheses that: 1) WASP activity is crucial for both the generation of marginal zone (MZ) B cells and homeostasis of functional T-regulatory cells (TR); and that these observations help to explain the susceptibility to infection with encapsulated bacteria, and the high-incidence of autoimmunity in WAS patients, respectively. Further, we predict that LV gene therapy will rescue these key defects. 2) Lentiviral vectors containing a pan-hematopoeitic or selected lymphoid restricted promoters will lead to functional correction of lymphoid development, activation, and survival; platelet turnover; and immune function in vivo in an animal model of WAS. 3) Analysis of viral marking and expression in a non-human primate model will allow us to define the optimal vector for use in human clinical trials; and provide key data with regard to any potential toxicity of this vector and/or dysregulated WASP expression within HSC and their progeny. Our proposed studies will provide nearly all of the key expression, efficacy, and safety data required to move forward with a human gene therapy trial for WAS; and have a very high likelihood for translation into new therapies.

描述（由申请人提供）： 该提案旨在开发一种有效且安全的 Wiskott-Aldrich 综合征 (WAS) 基因治疗临床前模型。虽然使用 HLA 匹配的骨髓移植可以治愈年轻的 WAS 患者，但成功率随着年龄的增长而急剧下降。多种证据证明表达 WASP 的造血细胞亚群具有强大的选择优势，表明将正常 WASP 基因引入造血干细胞 (HSC) 可以为疾病管理提供可行的治疗替代方案。虽然概念上很简单，但开发安全有效的 WASP 基因替换策略需要在人类和动物系统中进行广泛的临床前建模。该提案利用综合专业知识以及重要研究和临床合作者网络，建立一个慢病毒传递系统，用于 WAS 的最终基因治疗。我们将测试以下假设：1) WASP 活性对于边缘区 (MZ) B 细胞的生成和功能性 T 调节细胞 (TR) 的稳态至关重要；这些观察结果分别有助于解释 WAS 患者对封装细菌感染的易感性以及自身免疫的高发生率。此外，我们预测慢病毒基因治疗将挽救这些关键缺陷。 2）含有泛造血或选择性淋巴限制性启动子的慢病毒载体将导致淋巴发育、激活和存活的功能校正；血小板周转； WAS 动物模型中的体内免疫功能和免疫功能。 3) 在非人类灵长类动物模型中分析病毒标记和表达将使我们能够定义用于人类临床试验的最佳载体；并提供有关该载体的任何潜在毒性和/或 HSC 及其后代中 WASP 表达失调的关键数据。我们提出的研究将提供推进 WAS 人类基因治疗试验所需的几乎所有关键表达、功效和安全性数据；并且很有可能转化为新疗法。