SC Pneumologia - Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Curr Opin Pulm Med. 2019 May;25(3):294-299. doi: 10.1097/MCP.0000000000000576.
Pulmonary alveolar proteinosis (PAP) is characterized by the massive accumulation of lipoproteinaceous material within alveoli, which results in progressive respiratory failure. The abnormalities in surfactant clearance are caused by defective pulmonary macrophages, whose terminal differentiation is GM-CSF-dependent. In hereditary PAP, the rupture of GM-CSF signaling is because of mutations in the GM-CSF receptor genes. This review focus on the innovative technologies of gene-correction proposed for the development of new therapeutic strategies, for hereditary PAP patients.
Hematopoietic stem cell gene therapy has been successfully experimented in murine models to restore the expression of the GM-CSF receptor, however, a therapeutic approach based on bone marrow transplantation requires a preconditioning, which could be hazardous in PAP patients, who are highly susceptible to pulmonary infections. Gene-corrected pulmonary macrophages, administered directly to the lung, could represent an improved approach. Finally, patient-derived induced pluripotent stem cells seem to be promising to overcome the limited availability of primary patient cells and to generate gene-corrected macrophages, able to recover pulmonary surfactant clearance.
WLL is the gold standard therapy for PAP. However, its use in hereditary PAP is limited by the difficulty of performing this technique in paediatric patients and by its purely symptomatic efficacy. The recent advances in genome engineering could provide efficacious strategies for clinical application.
肺泡蛋白沉积症（PAP）的特征是肺泡内大量脂蛋白物质的积聚，导致进行性呼吸衰竭。表面活性剂清除异常是由于肺巨噬细胞缺陷引起的，其终末分化依赖于 GM-CSF。在遗传性 PAP 中，GM-CSF 信号的破裂是因为 GM-CSF 受体基因的突变。这篇综述重点介绍了为遗传性 PAP 患者开发新的治疗策略而提出的基因校正的创新技术。
造血干细胞基因治疗已在小鼠模型中成功实验，以恢复 GM-CSF 受体的表达，然而，基于骨髓移植的治疗方法需要预处理，这在 PAP 患者中可能是危险的，因为 PAP 患者极易发生肺部感染。直接给予肺部的基因校正的肺巨噬细胞可能是一种改进的方法。最后，患者来源的诱导多能干细胞似乎有希望克服原代患者细胞可用性有限的问题，并产生能够恢复肺表面活性剂清除的基因校正的巨噬细胞。
全肺灌洗（WLL）是 PAP 的金标准治疗方法。然而，其在遗传性 PAP 中的应用受到限制，因为在儿科患者中进行这项技术具有难度，并且其疗效仅为对症治疗。基因组工程的最新进展可为临床应用提供有效的策略。
