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

摘要 基因互补和肺巨噬细胞移植（PMT疗法）是一种有前途的潜力 进行性肺泡表面活性物质异常--遗传性肺泡蛋白沉积症的治疗 积累和呼吸衰竭-没有药物治疗。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再生能力丧失引起的。 受体信号传导和肺泡巨噬细胞（AM）功能的破坏，包括从肺泡巨噬细胞中去除表面活性剂， 肺泡我们证明了慢病毒载体介导的功能破坏CSF 2 RA突变的互补 在人AM中恢复GM-CSF受体信号传导，包括挽救表面活性剂清除。尽管如此， 研究进展，包括在两个国家证明PMT治疗的安全性、耐受性、有效性和持久性。 经过验证的hPAP动物模型，缺乏PMT治疗在人类中的临床研究是其毛皮的关键障碍， 治疗发展。我们的长期目标是将PMT疗法发展为一种有效的， hPAP的特异性治疗（以及可能的其他疾病）。这里的目标是完成筹备工作， 然后进行I期试验，以确定PMT在hPAP患者中的安全性，并确定 有用的临床和生物学结局指标，为未来II期疗效试验的设计提供信息。 中心假设是，自体CD 34+细胞衍生的CSF 2 RA基因校正的宏- 在没有骨髓消融的情况下，移植的细胞将存活，植入，采用表型和功能， 正常AM，替换内源性AM，重建保留在肺中的正常大小的AM群体 并产生安全、耐受性好、有效和持久的治疗益处。建议的理由 一项“首次在人体”的研究确定了PMT疗法在人类中的安全性， PMT疗法的临床开发，包括为未来开展II期临床疗效试验做准备。 我们计划通过在R61阶段追求四个具体目标和在R33阶段追求三个目标来解决我们的假设 阶段：1）完成CSF 2 RA基因校正的巨噬细胞的稳定性试验; 2）完成试验相关试验和3） IND相关文件; 4）获得监管机构批准（机构审查委员会和生物安全委员会， 数据、安全性和监测委员会，FDA）; 5）评估安全性，6）测量药代动力学和药物动力学参数。 macodynamics，和7）识别PMT治疗的临床结果和生物学特征的有用措施， 在hPAP患者中，拟议的研究是创新的，因为它代表了一个显着的背离， 目前的治疗方法，全肺灌洗（一种侵入性的、低效的物理去除表面的程序， tant）通过在hPAP患者中建立一种新方法来恢复GM-CSF应答的可行性， 功能性AM群体。这项研究是重要的，因为建立安全性， 在人类中，确定PMT疗法的有用临床结果指标是 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。

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.