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

人类基因转移

基本信息

批准号：
10179934
负责人：
JEFFREY P KRISCHER
金额：
$ 41.06万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179934
关键词：
Ablation Address Adopted Adult Adverse event Advisory Committees Age-Months Alveolar Alveolar Macrophages Animal Model Autologous Autologous Transplantation Biological Biological Markers Bone Marrow Bone Marrow Purging Bronchoalveolar Lavage CD34 gene CSF2RA gene Cell Therapy Cell Transplantation Cells Child Childhood Clinical Clinical Protocols Clinical Research Clinical Trials Clinical Trials Data Monitoring Committees Complement Development Diagnosis Diagnostic Disease Dose Drug Kinetics Engraftment Excision Feedback Formulation Functional disorder Future Gene Transfer Genes Goals Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Receptors Growth Health Health Status Homeostasis Human Informed Consent Inherited Institutional Review Boards Intervention Investigation Investigational Drugs Investigational New Drug Application Knowledge Lead Lentivirus Vector Lung Lung diseases Measures Mediating Medical Medical center Mission Morbidity - disease rate Mus Mutation Myeloid Cells Outcome Outcome Measure Pamphlets Pathogenesis Patients Pharmacotherapy Phase Phenotype Physiological Population Preparation Procedures Proliferating Public Health Pulmonary Alveolar Proteinosis Pulmonary Surfactants Quality of life Radiology Specialty Receptor Signaling Reporting Research Research Personnel Resources Respiratory Failure Safety Serious Adverse Event Severities Signal Transduction Therapeutic Time Toxicology Transplantation United States National Institutes of Health base clinical center clinical development clinical outcome measures cohort design driving force efficacy clinical trial efficacy study efficacy trial first-in-human gene complementation gene correction human study in vivo innovation institutional biosafety committee macrophage mouse model nonhuman primate novel strategies pediatric patients pharmacokinetics and pharmacodynamics phase 2 study phase I trial programs pulmonary function response self-renewal stability testing supplemental oxygen surfactant therapeutic development transplantation therapy

项目摘要

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.

抽象的基因互补和肺巨噬细胞移植（PMT疗法）潜力巨大遗传性肺泡蛋白沉积症（hPAP）的治疗——一种进行性肺泡表面活性物质紊乱蓄积和呼吸衰竭——我们对此没有明确的病理治疗方法。 hPAP 的发生、表现、诊断和治疗，表明它是由 GM-CSF 重新丧失引起的。受体信号传导和肺泡巨噬细胞 (AM) 功能的破坏，包括去除表面活性剂我们证明了慢病毒载体介导的功能破坏性 CSF2RA 突变的互补作用。恢复人类 AM 中的 GM-CSF 受体信号传导，包括挽救表面活性剂清除率。进展，包括在两种情况下证明 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，缺乏对人类 PMT 疗法的临床研究是其进一步发展的关键障碍。我们的长期目标是将 PMT 疗法开发为一种有效的疾病治疗方法。 hPAP（以及可能的其他疾病）的具体治疗此处的目标是完成治疗的准备工作，以及然后进行 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测量为未来 II 期疗效试验的设计提供信息。中心假设是，自体 CD34+ 细胞来源的 CSF2RA 基因校正后的 PMT 后，宏观- 噬菌体无需清髓，移植细胞将存活、移植并采用噬菌体的表型和功能正常 AM，替换内源性 AM，重建保留在肺部的正常大小的 AM 群体并产生安全、耐受性良好、有效且持久的治疗益处。研究表明，一项“首次人体”研究证实了 PMT 疗法在人类中的安全性，这将进一步解除障碍 PMT 疗法的临床开发，包括为未来进行 2 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 CSF2RA 基因校正巨噬细胞的稳定性测试；完成 2) 试验相关和 3) IND相关文件；4）获得监管部门的批准（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物宏观动力学，7) 确定 PMT 治疗的临床结果和生物学特征的有用测量方法拟议的研究具有创新性，因为它明显偏离了 hPAP 患者的研究。目前的治疗方法是全肺灌洗（一种侵入性、低效的物理去除表面活性物质的程序） tant）通过在 hPAP 患者中建立恢复 GM-CSF 反应的新方法的可行性，拟议的研究具有重要意义，因为建立了安全性、药代动力学。遗传学和药效学，并确定 PMT 疗法在人类中有用的临床结果测量我们临床研究计划的下一步是开发 PMT 作为 hPAP 的第一个特异性疗法。