R33HL156888

Human Gene Transfer & Macrophage Cell Transplantation Therapy of Hereditary PAP (HPAP) - Abstract

Gene complementation and pulmonary macrophage transplantation (PMT therapy) is a promising potential therapy of hereditary pulmonary alveolar proteinosis (HPAP) – a disorder of progressive alveolar surfactant accumulation and respiratory failure – for which no pharmacotherapy therapy exists.

We defined the pathogenesis, presentation, diagnosis, and management of HPAP, showed it is caused by the loss of GM-CSF receptor 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 outstanding 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 further therapeutic development.

Our long-term goal is to develop PMT therapy as 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 macrophages 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;
2) Complete 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 pharmacodynamics, and
7) Identify useful measures of the clinical outcomes and biological signature of PMT therapy 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 surfactant) 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, pharmacokinetics 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.

Childrens Hospital Medical Center

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Cincinnati, Ohio 45229 United States

Single Zip Code

NHLBI Early Phase Clinical Trials for Therapeutics and/or Diagnostics (R61/R33 Clinical Trial Required) (PAR-18-683)

Amendment Since initial award the total obligations have increased 143% from $2,085,135 to $5,062,198.