通过慢病毒载体介导的蛋白质表达纠正慢性肺部疾病。

Correction of a chronic pulmonary disease through lentiviral vector-mediated protein expression.

作者信息

Lund-Palau Helena, Juarez-Molina Claudia Ivette, Meng Cuixiang, Bhargava Anushka, Pilou Aikaterini, Aziz Kiran, Clarke Nora, Atsumi Naoko, Ashek Ali, Wilson Michael R, Takata Masao, Padley Simon, Gill Deborah R, Hyde Stephen C, Morgan Cliff, Alton Eric W F W, Griesenbach Uta

机构信息

National Heart and Lung Institute, Gene Therapy Group, Imperial College London, Faculty of Medicine, Manresa Road, London SW3 6LR, UK.

UK Respiratory Gene Therapy Consortium, London SW3 6LR, UK.

出版信息

Mol Ther Methods Clin Dev. 2022 Apr 14;25:382-391. doi: 10.1016/j.omtm.2022.04.002. eCollection 2022 Jun 9.

DOI:10.1016/j.omtm.2022.04.002

PMID:35573048

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9065048/

Abstract

We developed a novel lentiviral vector, pseudotyped with the F and HN proteins from Sendai virus (rSIV.F/HN), that produces long-lasting, high-efficiency transduction of the respiratory epithelium. Here we addressed whether this platform technology can secrete sufficient levels of a therapeutic protein into the lungs to ameliorate a fatal pulmonary disease as an example of its translational capability. Pulmonary alveolar proteinosis (PAP) results from alveolar granulocyte-macrophage colony-stimulating factor (GM-CSF) insufficiency, resulting in abnormal surfactant homeostasis and consequent ventilatory problems. Lungs of GM-CSF knockout mice were transduced with a single dose of rSIV.F/HN-expressing murine GM-CSF (mGM-CSF; 1e5-92e7 transduction units [TU]/mouse); mGM-CSF expression was dose related and persisted for at least 11 months. PAP disease biomarkers were rapidly and persistently corrected, but we noted a narrow toxicity/efficacy window. rSIV.F/HN may be a useful platform technology to deliver therapeutic proteins for lung diseases requiring long-lasting and stable expression of secreted proteins.

摘要

我们开发了一种新型慢病毒载体，其假型为仙台病毒的F和HN蛋白（rSIV.F/HN），可对呼吸道上皮进行持久、高效的转导。在此，我们探讨了该平台技术能否向肺部分泌足够水平的治疗性蛋白，以改善一种致命性肺部疾病，以此作为其转化能力的一个实例。肺泡蛋白沉积症（PAP）是由肺泡粒细胞-巨噬细胞集落刺激因子（GM-CSF）不足引起的，导致表面活性剂稳态异常及随之而来的通气问题。用单剂量表达鼠GM-CSF（mGM-CSF；1×10⁵-9.2×10⁷转导单位[TU]/小鼠）的rSIV.F/HN转导GM-CSF基因敲除小鼠的肺；mGM-CSF的表达与剂量相关，并持续至少11个月。PAP疾病生物标志物迅速且持续得到纠正，但我们注意到毒性/疗效窗口较窄。rSIV.F/HN可能是一种有用的平台技术，可用于递送治疗性蛋白，以治疗需要分泌蛋白长期稳定表达的肺部疾病。