Human gene transfer & macrophage cell transplantation therapy of hereditary PAP (hPAP)

摘要 基因互补与肺巨噬细胞移植(PMT治疗)是一种很有前途的治疗方法 遗传性肺泡蛋白沉积症的治疗--一种进行性肺泡表面活性物质紊乱 积聚和呼吸衰竭--目前尚无药物治疗方法。我们定义了病态- HPAP的发生、表现、诊断和治疗表明，它是由GM-CSF受体缺失引起的。 受体信号转导和肺泡巨噬细胞(AM)功能的破坏，包括表面活性物质从 肺泡。我们证明了慢病毒载体介导的功能扰乱CSF2RA突变的互补 恢复人肺泡巨噬细胞GM-CSF受体信号，包括挽救表面活性物质清除。尽管很突出- ING进展，包括在两年内证明PMT疗法的安全性、耐受性、有效性和持久性 经过验证的HPAP动物模型，缺乏人类PMT疗法的临床研究是其发展的关键障碍。 进一步的治疗进展。我们的长期目标是将PMT疗法发展为一种有效的疾病- HPAP(可能还有其他疾病)的特定治疗。这里的目标是完成以下各项的准备工作 然后进行一项I期试验，以确定PMT在人类HPAP患者中的安全性，并确定 有用的临床和生物学结果指标，为未来第二阶段疗效试验的设计提供信息。 中心假说是自体CD34+细胞来源的CSF2RA基因经PMT后宏观校正。 噬菌体在没有骨髓清除剂的情况下，移植的细胞会存活，植入，采用表型和功能 正常AM，取代内源性AM，重建留在肺内的正常大小AM种群 并产生安全、耐受性好、有效和持久的治疗益处。建议的理由是 研究表明，一项确定PMT疗法在人类中的安全性的首个人类研究将进一步打开障碍 PMT疗法的临床发展包括为进行未来的第二阶段临床疗效试验做准备。 我们计划通过在R61阶段实现四个具体目标和在R33阶段实现三个目标来解决我们的假设 阶段：1)完成CSF2RA基因修饰的巨噬细胞的稳定性测试；完成2)试验相关和3) 与IND相关的文件；4)获得监管批准(机构审查委员会和生物安全委员会， 数据，安全和监测委员会，FDA)；5)评估安全性，6)测量药代动力学和药效- 宏观动力学，以及7)确定PMT治疗的临床结果和生物学特征的有用测量- HPAP患者的APY。这项拟议的研究具有创新性，因为它代表了与 目前的治疗方法是全肺灌洗(一种侵入性的、低效的物理去除表面的程序)。 Ant)通过在HPAP患者中建立一种新的方法来恢复GM-CSF反应的可行性， 功能AM群体。这项拟议的研究具有重要意义，因为建立了安全性、药理学- 人类PMT疗法的奈特学和药效学，以及确定有用的临床结果指标 我们临床研究计划的下一步是开发PMT作为HPAP的第一种特异性治疗方法。

ABSTRACT Gene complementation and pulmonary macrophage transplantation (PMT Therapy) is a promising potential therapy of hereditary pulmonary alveolar proteinosis (hPAP) – a disorder of progressive of alveolar surfactant accumulation and respiratory failure – for which no pharmacotherapy therapy exists. We defined the patho- genesis, presentation, diagnosis, and management of hPAP, showed it is caused by the loss of GM-CSF re- ceptor signaling and disruption of alveolar macrophage (AM) functions including the removal of surfactant from alveoli. We demonstrated lentiviral vector-mediated complementation of function-disrupting CSF2RA mutations restored GM-CSF receptor signaling in human AMs including rescue of surfactant clearance. Despite outstand- ing progress, including demonstration of the safety, tolerability, efficacy, and durability of PMT Therapy in two validated hPAP animal models, lack of clinical studies of PMT Therapy in humans is a critical barrier to its fur- ther therapeutic development. Our long-term goal is to develop PMT Therapy as the an effective, disease- specific therapy of hPAP (and possibly other diseases). The objective here is to complete preparations for, and then to conduct, a Phase I trial to establish the safety of PMT in human patients with hPAP and also identify useful clinical and biological outcome measures informing the design of a future Phase II efficacy trial. The central Hypothesis is that after PMT of autologous CD34+ cell-derived CSF2RA gene-corrected macro- phages without myeloablation, the transplanted cells will survive, engraft, adopt the phenotype and function of normal AMs, replace endogenous AMs, reestablish a normal-sized AM population that remains in the lungs and results in a safe, well-tolerated, effective, and durable treatment benefit. The rationale for the proposed research is that a ‘first-in-human’ study establishing the safety of PMT Therapy in humans will unblock further clinical development of PMT Therapy including preparation for conduct of a future phase 2 clinical efficacy trial. We plan to address our hypothesis by pursuing four specific aims in the R61 phase and three aims in the R33 phase: 1) finalize stability testing of CSF2RA gene-corrected macrophages; complete 2) trial-related and 3) IND-related documents; 4) obtain regulatory approvals (Institutional Review Board and Biosafety Committee, Data, Safety, and Monitoring Board, FDA); 5) assess the safety, 6) measure the pharmacokinetics and phar- macodynamics, and 7) identify useful measures of the clinical outcomes and biological signature of PMT Ther- apy in hPAP patients. The proposed research is innovative because it represents a marked departure from the current treatment approach, whole lung lavage (an invasive, inefficient, procedure to physically remove surfac- tant) by establishing, in hPAP patients, the feasibility of a new approach to restore a GM-CSF-responsive, functional AM population. The proposed research is significant because establishing the safety, pharmacoki- netics and pharmacodynamics, and identifying useful clinical outcome measures of PMT Therapy in humans is the next step in our clinical research program to develop PMT as the first specific therapy of hPAP.