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基因治疗造血干细胞和祖细胞治疗单基因疾病的系统评价和荟萃分析。

A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders.

机构信息

Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy.

出版信息

Nat Commun. 2022 Mar 14;13(1):1315. doi: 10.1038/s41467-022-28762-2.

DOI:10.1038/s41467-022-28762-2
PMID:35288539
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8921234/
Abstract

Ex-vivo gene therapy (GT) with hematopoietic stem and progenitor cells (HSPCs) engineered with integrating vectors is a promising treatment for monogenic diseases, but lack of centralized databases is hampering an overall outcomes assessment. Here we aim to provide a comprehensive assessment of the short and long term safety of HSPC-GT from trials using different vector platforms. We review systematically the literature on HSPC-GT to describe survival, genotoxicity and engraftment of gene corrected cells. From 1995 to 2020, 55 trials for 14 diseases met inclusion criteria and 406 patients with primary immunodeficiencies (55.2%), metabolic diseases (17.0%), haemoglobinopathies (24.4%) and bone marrow failures (3.4%) were treated with gammaretroviral vector (γRV) (29.1%), self-inactivating γRV (2.2%) or lentiviral vectors (LV) (68.7%). The pooled overall incidence rate of death is 0.9 per 100 person-years of observation (PYO) (95% CI = 0.37-2.17). There are 21 genotoxic events out of 1504.02 PYO, which occurred in γRV trials (0.99 events per 100 PYO, 95% CI = 0.18-5.43) for primary immunodeficiencies. Pooled rate of engraftment is 86.7% (95% CI = 67.1-95.5%) for γRV and 98.7% (95% CI = 94.5-99.7%) for LV HSPC-GT (p = 0.005). Our analyses show stable reconstitution of haematopoiesis in most recipients with superior engraftment and safer profile in patients receiving LV-transduced HSPCs.

摘要

体外基因治疗（GT）使用整合载体对造血干细胞和祖细胞（HSPCs）进行基因工程改造，是治疗单基因疾病的一种很有前途的方法，但缺乏集中的数据库阻碍了对整体结果的评估。在这里，我们旨在提供使用不同载体平台的 HSPC-GT 试验的短期和长期安全性的综合评估。我们系统地回顾了 HSPC-GT 的文献，以描述基因校正细胞的存活、遗传毒性和植入情况。从 1995 年到 2020 年，有 55 项针对 14 种疾病的试验符合纳入标准，共有 406 名原发性免疫缺陷症（55.2%）、代谢疾病（17.0%）、血红蛋白病（24.4%）和骨髓衰竭症（3.4%）患者接受了γ逆转录病毒载体（γRV）（29.1%）、自我失活的γRV（2.2%）或慢病毒载体（LV）（68.7%）治疗。观察期间每 100 人年的总死亡率为 0.9（95%CI=0.37-2.17）。在 1504.02 人年中发生了 21 例遗传毒性事件，其中 2 例发生在 γRV 试验中（每 100 人年发生 0.99 例，95%CI=0.18-5.43），用于原发性免疫缺陷症。γRV 和 LV HSPC-GT 的植入率分别为 86.7%（95%CI=67.1-95.5%）和 98.7%（95%CI=94.5-99.7%）（p=0.005）。我们的分析表明，大多数接受者的造血功能稳定重建，接受 LV 转导的 HSPC 治疗的患者具有更好的植入效果和更安全的特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f3b/8921234/8e65f99e0068/41467_2022_28762_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f3b/8921234/3118306d96ce/41467_2022_28762_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f3b/8921234/8e65f99e0068/41467_2022_28762_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f3b/8921234/5fbb8789d0c5/41467_2022_28762_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f3b/8921234/41b538be5544/41467_2022_28762_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f3b/8921234/d7eef26cc6d4/41467_2022_28762_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8f3b/8921234/3118306d96ce/41467_2022_28762_Fig4_HTML.jpg
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