Gene Therapy of [beta]c-Deficient Pulmonary Alveolar Proteinosis ([beta]c-PAP): Studies in a Murine in vivo Model

Pulmonary alveolar proteinosis (PAP) due to deficiency of the common β-chain (βc) of the interleukin-3 (IL-3)/IL-5/granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors is a rare monogeneic disease characterized by functional insufficiency of pulmonary macrophages. Hematopoietic stem c...

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Veröffentlicht in:Molecular therapy 2008-04, Vol.16 (4), p.757
Hauptverfasser: Kleff, Veronika, Sorg, Ursula R, Bury, Carsten, Suzuki, Takuji, Rattmann, Ina, Jerabek-willemsen, Moran, Poremba, Christopher, Flasshove, Michael, Opalka, Bertram, Trapnell, Bruce, Dirksen, Uta, Moritz, Thomas
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Sprache:eng
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Zusammenfassung:Pulmonary alveolar proteinosis (PAP) due to deficiency of the common β-chain (βc) of the interleukin-3 (IL-3)/IL-5/granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors is a rare monogeneic disease characterized by functional insufficiency of pulmonary macrophages. Hematopoietic stem cell gene therapy for restoring expression of βc-protein in the hematopoietic system may offer a curative approach. Toward this end, we generated a retroviral construct expressing the murine βc (mβc) gene and conducted investigations in a murine model of βc-deficient PAP. Functional correction of mβc activity in mβc -/- bone marrow (BM) cells was demonstrated by restoration of in vitro colony formation in response to GM-CSF. In addition, in a murine in vivo model of mβc-deficient PAP mβc gene transfer to hematopoietic stem cells not only restored the GM-CSF-sensitivity of hematopoietic progenitor cells but also, within a period of 12 weeks, almost completely reversed the morphologic features of surfactant accumulation. These results were obtained despite modest transduction levels (10-20%) and, in comparison to wild-type mice, clearly reduced βc expression levels were detected in hematopoietic cells. Therefore, our data demonstrating genetic and functional correction of mβc -/- deficiency in vitro as well as in a murine in vivo model of PAP strongly suggest gene therapy as a potential new treatment modality in βc-deficient PAP.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2008.7