# Human gene transfer & macrophage cell transplantation therapy of hereditary PAP (hPAP) > **NIH NIH R61** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $410,607 ## Abstract 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 signific... ## Key facts - **NIH application ID:** 10179934 - **Project number:** 1R61HL156888-01 - **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR - **Principal Investigator:** JEFFREY P KRISCHER - **Activity code:** R61 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $410,607 - **Award type:** 1 - **Project period:** 2021-05-10 → 2023-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10179934 ## Citation > US National Institutes of Health, RePORTER application 10179934, Human gene transfer & macrophage cell transplantation therapy of hereditary PAP (hPAP) (1R61HL156888-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179934. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*