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

人类基因转移

• 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
• 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

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 基因完成和肺巨噬细胞移植（PMT治疗）是有望的潜力 遗传性肺肺泡蛋白质病（HPAP）的疗法 - 肺泡表面活性剂进行性疾病 积累和呼吸衰竭 - 不存在药物治疗。我们定义了病情 HPAP的起源，表现，诊断和管理，这表明这是由于GM-CSF的丧失引起的 肺泡巨噬细胞（AM）功能的呼吸器信号传导和破坏，包括从中去除表面活性剂 肺泡。我们证明了慢病毒媒介介导的csf2ra突变的功能干扰的完成 在人类AM中恢复的GM-CSF接收器信号传导，包括拯救表面活性剂清除率。尽管出色 - 进度，包括在两个 经过验证的HPAP动物模型，缺乏人类PMT治疗的临床研究是其毛皮的关键障碍 治疗性开发。我们的长期目标是开发PMT疗法作为一种有效的疾病 - HPAP的特定疗法（可能是其他疾病）。这里的目的是完成准备和 然后进行进行I期试验，以确定PMT在HPAP患者中的安全性，也确定 有用的临床和生物学结局指标，告知未来II期有效试验的设计。 中心假设是自体CD34+细胞衍生的CSF2RA基因校正的宏观 - 没有骨髓化的噬菌体，移植的细胞将生存，植入，采用表型和功能 正常AMS，替换内源性AM，重建保留在肺部的正常大小的AM种群 并导致安全，耐受性良好，有效且耐用的治疗益处。提议的理由 研究是一项“人类的第一届”研究，建立PMT治疗在人类中的安全性将进一步解除 PMT治疗的临床发展，包括准备未来的2阶段临床效率试验。 我们计划通过在R61阶段追求四个特定目标来解决我们的假设，而R33的三个目标 阶段：1）最终确定CSF2RA基因校正巨噬细胞的稳定性测试；完整2）与试验有关的和3） 与IND相关的文件； 4）获得法规批准（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）衡量药代动力学和PHAR- Macodynemics和7）确定对PMT治疗的临床结果和生物学特征的有用测量 HPAP患者的APY。拟议的研究具有创新性，因为它代表了与 当前的治疗方法，全肺灌洗（一种侵入性，效率低下的程序，可以物理去除表面 通过在HPAP患者中建立一种新方法来恢复GM-CSF响应的新方法的可行性， 功能性AM人群。拟议的研究很重要，因为建立安全性，药物的安全性 网络学和药效学，并确定人类PMT治疗的有用的临床结果指标是 我们的临床研究计划的下一步是开发PMT作为HPAP的第一个特定疗法。