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用于X连锁重症联合免疫缺陷基因治疗的慢病毒载体的临床前开发

Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency.

作者信息

Poletti Valentina, Charrier Sabine, Corre Guillaume, Gjata Bernard, Vignaud Alban, Zhang Fang, Rothe Michael, Schambach Axel, Gaspar H Bobby, Thrasher Adrian J, Mavilio Fulvio

机构信息

Genethon, Evry, France.

University College London, Great Ormond Street Institute of Child Health, London, UK.

出版信息

Mol Ther Methods Clin Dev. 2018 Mar 10;9:257-269. doi: 10.1016/j.omtm.2018.03.002. eCollection 2018 Jun 15.

DOI:10.1016/j.omtm.2018.03.002
PMID:29707600
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5918176/
Abstract

X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the interleukin-2 receptor γ chain gene (IL2RG), and it is characterized by profound defects in T, B, and natural killer (NK) cell functions. Transplantation of hematopoietic stem/progenitor cells (HSPCs) genetically corrected with early murine leukemia retrovirus (MLV)-derived gammaretroviral vectors showed restoration of T cell immunity in patients, but it resulted in vector-induced insertional oncogenesis. We developed a self-inactivating (SIN) lentiviral vector carrying a codon-optimized human IL2RG cDNA driven by the EF1α short promoter (EFS-IL2RG), and we tested its efficacy and safety by transplanting transduced Il2rg-deficient Lin HSPCs in an / mouse model. The study showed restoration of T, B, and NK cell counts in bone marrow and peripheral blood and normalization of thymus and spleen cellularity and architecture. High-definition insertion site analysis defined the EFS-IL2RG genomic integration profile, and it showed no sign of vector-induced clonal selection or skewing in primarily and secondarily transplanted animals. The study enables a phase I/II clinical trial aimed at restoring both T and B cell immunity in SCID-X1 children upon non-myeloablative conditioning.

摘要

X连锁重症联合免疫缺陷（SCID-X1）由白细胞介素-2受体γ链基因（IL2RG）突变引起，其特征为T、B和自然杀伤（NK）细胞功能存在严重缺陷。用早期鼠白血病逆转录病毒（MLV）衍生的γ逆转录病毒载体进行基因校正的造血干/祖细胞（HSPCs）移植，显示患者的T细胞免疫功能得以恢复，但导致了载体诱导的插入性肿瘤发生。我们构建了一种自我失活（SIN）慢病毒载体，其携带由EF1α短启动子（EFS）驱动的密码子优化的人IL2RG cDNA（EFS-IL2RG），并通过在Il2rg缺陷的Lin小鼠模型中移植转导的HSPCs来测试其疗效和安全性。该研究显示骨髓和外周血中T、B和NK细胞计数恢复，胸腺和脾脏细胞数量及结构正常化。高清插入位点分析确定了EFS-IL2RG的基因组整合图谱，并且在初次和二次移植的动物中均未显示载体诱导的克隆选择或偏倚迹象。该研究使得开展一项I/II期临床试验成为可能，该试验旨在通过非清髓性预处理恢复SCID-X1儿童的T和B细胞免疫功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/57eff47833eb/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/0e1b57bcbdb8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/4e9dc91ce7e7/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/442d1f9077f8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/336058f0e208/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/8267dd5fdfbc/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/57eff47833eb/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/0e1b57bcbdb8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/4e9dc91ce7e7/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/442d1f9077f8/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/336058f0e208/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/8267dd5fdfbc/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d8e4/5918176/57eff47833eb/gr6.jpg

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