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

人类基因转移

基本信息

批准号：
10702185
负责人：
JEFFREY P KRISCHER
金额：
$ 213.2万
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 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10702185
关键词：
Ablation Address Adopted Adult Adverse event Advisory Committees Age Months Alveolar Alveolar Macrophages Alveolus Animal Model Autologous Autologous Transplantation Biological Biological Markers Bone Marrow Bone Marrow Purging Bronchoalveolar Lavage CD34 gene CSF2RA gene Cell Proliferation 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 Good Manufacturing Process Granulocyte-Macrophage Colony-Stimulating Factor Granulocyte-Macrophage Colony-Stimulating Factor Receptors Growth Health Health Status Homeostasis Human Informed Consent Inherited Institution Institutional Review Boards Intervention Investigational Drugs Investigational New Drug Application Knowledge Lentivirus Vector Lung Lung diseases Macrophage Measures Mediating Medical Medical center Mission Morbidity - disease rate Mus Mutation Myeloid Cells Outcome Outcome Measure Pamphlets Pathogenesis Patients Pharmacodynamics Pharmacotherapy Phase Phenotype Physiological Population Preparation Procedures 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 Writing 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 improved in vivo innovation institutional biosafety committee manufacture mouse model nonhuman primate novel strategies pediatric patients pharmacokinetics and pharmacodynamics phase 2 study phase I trial programs pulmonary function response safety assessment 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.

摘要