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Gene Therapy for SCID-X1 with Low Dose Busulfan and a SIN-lentiviral Vector

使用低剂量白消安和 SIN 慢病毒载体对 SCID-X1 进行基因治疗

基本信息

批准号：
10827632
负责人：
DAVID A WILLIAMS
金额：
$ 128.56万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-07 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10827632
关键词：
Gene Therapy SCID X1 Low

项目摘要

Gene therapy using autologous C034+ cells is a promising treatment for primary immunodeficiency, particularly for individuals without optimal allogeneic donors. SCIO-X1 is caused by mutations in IL2RG, which encodes the common gamma chain (ye) of multiple cytokine receptors. Boys with SCIO-X1 lack T and NK cells, and their B cells fail to produce antibodies due to the lack of IL-7, IL-15 and IL-21 function respectively. This project seeks to test the efficacy and safety of a new self-inactivating lentiviral (LV) vector to treat SCIO- X1. We hypothesize that this trial will improve immune reconstitution through the introduction of low dose busulfan conditioning (Aim 1) and improve safety through the change from a gammaretroviral (yRV) vector used in previous trials to the LV vector in this trial (Aim 2). Previous trials of gene therapy for SCIO-X1 have infused cells without chemotherapy conditioning, which resulted in robust T cell recovery and gene marking, but negligible gene marking in B cells and failure of humoral immune reconstitution. Initial development and marking in NK cells was not sustained. In Aim 1 we will examine the impact of low dose busulfan conditioning on 1) cell type specific engraftment and gene marking, 2) in vivo T cell reconstitution, T cell phenotype and TRB repertoire by deep sequencing, 3) in vivo humoral immune reconstitution, B cell number, phenotype, IL-21 dependent function and IGH repertoire by deep sequencing, 4) NK cell number, phenotype and function. Previous trials of gene therapy for SCIO-X1 have used a yRV vector with intact viral promoters/enhancers, which resulted in 5/20 patients developing T cell leukemia due to insertional oncogenesis. Gene therapy using a self-inactivating yRV vector in which viral enhancers have been deleted shows encouraging evidence of reduced insertion sites near lymphoid oncogenes, but an initial insertion site pattern that is still risky. The proposed trial in this application will further improve safety by using a self-inactivating LV vector. In Aim 2 we will investigate the initial insertion site pattern in the patients' C034+ transduced cells and compare samples from the proposed trial to historical trials using yRV, analyze insertion site profile in peripheral blood after gene therapy to perform lineage tracing and compare clustering with samples from previous trials.

使用自体C 034+细胞的基因治疗是治疗原发性免疫缺陷的有希望的治疗方法，特别是对于没有最佳同种异体供体的个体。SCIO-X1由IL 2 RG突变引起，其编码多种细胞因子受体的共同γ链（Ye）。SCIO-X1男孩缺乏T 和NK细胞，以及它们的B细胞由于缺乏IL-7、IL-15和IL-21功能而不能产生抗体分别该项目旨在测试一种新的自失活慢病毒（LV）的有效性和安全性载体来治疗Scio。我们假设，这项试验将通过以下途径改善免疫重建：引入低剂量白消安预处理（目标1），并通过改变将先前试验中使用的γ逆转录病毒（yRV）载体与本试验中的LV载体进行比较（目的2）。以前的SCIO-X1基因治疗试验在没有化疗条件的情况下注入细胞，导致T细胞恢复和基因标记稳健，但B细胞中的基因标记可忽略不计，体液免疫重建。NK细胞的初始发育和标记没有持续。目标1 我们将研究低剂量白消安预处理对1）细胞类型特异性植入的影响，基因标记， 2)体内T细胞重建，通过深度测序的T细胞表型和TRB库，3）体内体液免疫重建、B细胞数量、表型、IL-21依赖功能和IGH库通过深度测序，4）NK细胞数量、表型和功能。先前的SCIO-X1基因治疗试验使用了具有完整病毒的yRV载体，启动子/增强子，这导致5/20例患者由于插入启动子/增强子而发生T细胞白血病。肿瘤发生使用自失活yRV载体的基因治疗，其中病毒增强子已被删除显示了淋巴癌基因附近插入位点减少的令人鼓舞的证据，但最初的研究表明，插入位点模式仍然是有风险的。本申请中的拟议试验将通过以下方式进一步提高安全性：用的是一种自失活的左心室载体在目标2中，我们将研究在细胞中的初始插入位点模式。患者的C 034+转导细胞，并使用 yRV，分析基因治疗后外周血中的插入位点谱以进行谱系追踪，将聚类与之前试验的样本进行比较。