A toxicology study of Csf2ra complementation and pulmonary macrophage transplantation therapy of hereditary PAP in mice.

Autor:	Arumugam P; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA., Carey BC; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA., Wikenheiser-Brokamp KA; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA.; Division of Pathology & Laboratory Medicine, CCHMC, Cincinnati, OH, USA.; Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Krischer J; Departments of Pediatrics and Internal Medicine, University of South Florida, Morsani College of Medicine, Tampa, FL, USA., Wessendarp M; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA., Shima K; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA., Chalk C; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA., Stock J; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA., Ma Y; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA., Black D; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA., Imbrogno M; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, UCMC, Cincinnati, OH, USA., Collins M; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, UCMC, Cincinnati, OH, USA., Kalenda Yombo DJ; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, UCMC, Cincinnati, OH, USA., Sakthivel H; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA., Suzuki T; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA., Lutzko C; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.; Cell Manipulations Laboratory, CCHMC, Cincinnati, OH, USA., Cancelas JA; Division of Experimental Hematology, CCHMC, Cincinnati, OH, USA., Adams M; Office for Clinical and Translational Research, CCHMC, Cincinnati, OH, USA., Hoskins E; Office for Clinical and Translational Research, CCHMC, Cincinnati, OH, USA., Lowe-Daniels D; Translational Core Laboratory, CCHMC, Cincinnati, OH, USA., Reeves L; Translational Core Laboratory, CCHMC, Cincinnati, OH, USA., Kaiser A; Office of Research Compliance & Regulatory Affairs, CCHMC, Cincinnati, OH, USA., Trapnell BC; Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.; Division of Pulmonary Biology, Perinatal Institute, CCHMC, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, UCMC, Cincinnati, OH, USA.; Division of Pulmonary Medicine, CCHMC, Cincinnati, OH, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2024 Feb 17; Vol. 32 (2), pp. 101213. Date of Electronic Publication: 2024 Feb 17 (Print Publication: 2024).
DOI:	10.1016/j.omtm.2024.101213
Abstrakt:	Pulmonary macrophage transplantation (PMT) is a gene and cell transplantation approach in development as therapy for hereditary pulmonary alveolar proteinosis (hPAP), a surfactant accumulation disorder caused by mutations in CSF2RA/B (and murine homologs). We conducted a toxicology study of PMT of Csf2ra gene-corrected macrophages (mGM-Rα + Mϕs) or saline-control intervention in Csf2ra KO or wild-type (WT) mice including single ascending dose and repeat ascending dose studies evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. Lentiviral-mediated Csf2ra cDNA transfer restored GM-CSF signaling in mGM-Rα + Mϕs. Following PMT, mGM-Rα + Mϕs engrafted, remained within the lungs, and did not undergo uncontrolled proliferation or result in bronchospasm, pulmonary function abnormalities, pulmonary or systemic inflammation, anti-transgene product antibodies, or pulmonary fibrosis. Aggressive male fighting caused a similarly low rate of serious adverse events in saline- and PMT-treated mice. Transient, minor pulmonary neutrophilia and exacerbation of pre-existing hPAP-related lymphocytosis were observed 14 days after PMT of the safety margin dose but not the target dose (5,000,000 or 500,000 mGM-Rα + Mϕs, respectively) and only in Csf2ra KO mice but not in WT mice. PMT reduced lung disease severity in Csf2ra KO mice. Results indicate PMT of mGM-Rα + Mϕs was safe, well tolerated, and therapeutically efficacious in Csf2ra KO mice, and established a no adverse effect level and 10-fold safety margin. Competing Interests: B.C.T. has equity in Altius Therapeutics, a biopharmaceutical company with a license from Cincinnati Children’s Hospital Medical Center to develop PMT as a therapeutic platform beyond the planned clinical use as therapy of hPAP. (© 2024 The Authors.)
Databáze:	MEDLINE
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