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Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis.

遗传性肺泡蛋白沉积症小鼠模型中基于造血干细胞的有效基因治疗。

  • 影响因子:4.07
  • DOI:10.3324/haematol.2018.214866
  • 作者列表:"Hetzel M","Lopez-Rodriguez E","Mucci A","Nguyen AHH","Suzuki T","Shima K","Buchegger T","Dettmer S","Rodt T","Bankstahl JP","Malik P","Knudsen L","Schambach A","Hansen G","Trapnell BC","Lachmann N","Moritz T
  • 发表时间:2020-04-01
Abstract

:Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic stem cell-based gene therapy. Using Csf2rb-/- mice, a model closely reflecting the human herPAP disease phenotype, we here demonstrate robust pulmonary engraftment of an alveolar macrophage population following intravenous transplantation of lentivirally corrected hematopoietic stem and progenitor cells. Engraftment was associated with marked improvement of critical herPAP disease parameters, including bronchoalveolar fluid protein, cholesterol and cytokine levels, pulmonary density on computed tomography scans, pulmonary deposition of Periodic Acid-Schiff+ material as well as respiratory mechanics. These effects were stable for at least nine months. With respect to engraftment and alveolar macrophage differentiation kinetics, we demonstrate the rapid development of CD11c+/SiglecF+ cells in the lungs from a CD11c-/SiglecF+ progenitor population within four weeks after transplantation. Based on these data, we suggest hematopoietic stem cell-based gene therapy as an effective and cause-directed treatment approach for herPAP.

摘要

: 由于 GM-CSF 受体缺陷 (herPAP) 引起的遗传性肺泡蛋白沉积症构成了一种危及生命的肺部疾病,其特征是继发于肺泡巨噬细胞功能缺陷的肺泡表面活性蛋白沉积。由于目前的治疗选择主要是症状性的,我们已经探索了基于造血干细胞的基因治疗的潜力。使用 Csf2rb-/-小鼠,一个密切反映人类 herPAP 疾病表型的模型,我们在这里证明了静脉移植慢病毒校正的造血干细胞和祖细胞后肺泡巨噬细胞群的稳健肺植入。植入与严重 herPAP 疾病参数的显著改善相关,包括支气管肺泡灌洗液蛋白、胆固醇和细胞因子水平、计算机断层扫描肺密度,周期性酸-Schiff + 材料的肺沉积以及呼吸力学。这些效应稳定至少 9 个月。关于植入和肺泡巨噬细胞分化动力学,我们证明了 CD11c-/SiglecF + 祖细胞在移植后四周内在肺中快速发育。基于这些数据,我们建议以造血干细胞为基础的基因治疗作为 herPAP 的一种有效且以病因为导向的治疗方法。

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DOI:10.1111/bph.14861
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影响因子:3.94
发表时间:2020-01-15
DOI:10.1016/j.taap.2019.114847
作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

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影响因子:4.04
发表时间:2020-01-10
DOI:10.1042/BST20191010
作者列表:["Zaragosi LE","Deprez M","Barbry P"]

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