Molecular Therapy: Methods & Clinical Development (Jun 2024)

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

  • Paritha Arumugam,
  • Brenna C. Carey,
  • Kathryn A. Wikenheiser-Brokamp,
  • Jeffrey Krischer,
  • Matthew Wessendarp,
  • Kenjiro Shima,
  • Claudia Chalk,
  • Jennifer Stock,
  • Yan Ma,
  • Diane Black,
  • Michelle Imbrogno,
  • Margaret Collins,
  • Dan Justin Kalenda Yombo,
  • Haripriya Sakthivel,
  • Takuji Suzuki,
  • Carolyn Lutzko,
  • Jose A. Cancelas,
  • Michelle Adams,
  • Elizabeth Hoskins,
  • Dawn Lowe-Daniels,
  • Lilith Reeves,
  • Anne Kaiser,
  • Bruce C. Trapnell

Journal volume & issue
Vol. 32, no. 2
p. 101213

Abstract

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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 Csf2raKO 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 Csf2raKO mice but not in WT mice. PMT reduced lung disease severity in Csf2raKO mice. Results indicate PMT of mGM-Rα+Mϕs was safe, well tolerated, and therapeutically efficacious in Csf2raKO mice, and established a no adverse effect level and 10-fold safety margin.

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