Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Pulmonary Medicine, Jichi Medical University, Shimotsuke-shi, Tochigi-ken 329-0498, Japan.
Mol Ther. 2019 Sep 4;27(9):1597-1611. doi: 10.1016/j.ymthe.2019.06.010. Epub 2019 Jul 2.
Hereditary pulmonary alveolar proteinosis (PAP) is a genetic lung disease characterized by surfactant accumulation and respiratory failure arising from disruption of GM-CSF signaling. While mutations in either CSF2RA or CSF2RB (encoding GM-CSF receptor α or β chains, respectively) can cause PAP, α chain mutations are responsible in most patients. Pulmonary macrophage transplantation (PMT) is a promising new cell therapy in development; however, no studies have evaluated this approach for hereditary PAP (hPAP) caused by Csf2ra mutations. Here, we report on the preclinical safety, tolerability, and efficacy of lentiviral-vector (LV)-mediated Csf2ra expression in macrophages and PMT of gene-corrected macrophages (gene-PMT therapy) in Csf2ra gene-ablated (Csf2ra) mice. Gene-PMT therapy resulted in a stable transgene integration and correction of GM-CSF signaling and functions in Csf2ra macrophages in vitro and in vivo and resulted in engraftment and long-term persistence of gene-corrected macrophages in alveoli; restoration of pulmonary surfactant homeostasis; correction of PAP-specific cytologic, histologic, and biomarker abnormalities; and reduced inflammation associated with disease progression in untreated mice. No adverse consequences of gene-PMT therapy in Csf2ra mice were observed. Results demonstrate that gene-PMT therapy of hPAP in Csf2ra mice was highly efficacious, durable, safe, and well tolerated.
遗传性肺泡蛋白沉积症（PAP）是一种遗传性肺部疾病，其特征是表面活性剂积聚和呼吸衰竭，这是由于 GM-CSF 信号通路的破坏引起的。虽然 CSF2RA 或 CSF2RB（分别编码 GM-CSF 受体 α 或 β 链）的突变都可能导致 PAP，但大多数患者的突变发生在 α 链上。肺巨噬细胞移植（PMT）是一种有前途的新细胞治疗方法正在开发中；然而，尚无研究评估该方法用于 CSF2ra 突变引起的遗传性 PAP（hPAP）。在这里，我们报告了慢病毒载体（LV）介导的 CSF2ra 在巨噬细胞中的表达以及基因校正的巨噬细胞中的 PMT（基因-PMT 治疗）在 CSF2ra 基因敲除（Csf2ra）小鼠中的临床前安全性、耐受性和疗效。基因-PMT 治疗导致稳定的转基因整合和 GM-CSF 信号和功能在体外和体内的 CSF2ra 巨噬细胞中的校正，并导致基因校正的巨噬细胞在肺泡中的植入和长期持久存在；恢复肺表面活性剂的动态平衡；纠正 PAP 特异性细胞学、组织学和生物标志物异常；并减少未经治疗小鼠疾病进展相关的炎症。在 Csf2ra 小鼠中未观察到基因-PMT 治疗的不良后果。结果表明，在 Csf2ra 小鼠中进行 hPAP 的基因-PMT 治疗具有高效、持久、安全和良好的耐受性。
