• Veronika Kleff, Ursula R Sorg, Carsten Bury, Takuji Suzuki, Ina Rattmann, Moran Jerabek-Willemsen, Christopher Poremba, Michael Flasshove, Bertram Opalka, Bruce Trapnell, Uta Dirksen, and Thomas Moritz.
• Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Essen, Germany.
• Mol. Ther. 2008 Apr 1; 16 (4): 757-64.

AbstractPulmonary alveolar proteinosis (PAP) due to deficiency of the common beta-chain (beta(c)) 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 beta(c)-protein in the hematopoietic system may offer a curative approach. Toward this end, we generated a retroviral construct expressing the murine beta(c) (mbeta(c)) gene and conducted investigations in a murine model of beta(c)-deficient PAP. Functional correction of mbeta(c) activity in mbeta(c)(-/-) 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 mbeta(c)-deficient PAP mbeta(c) 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 beta(c) expression levels were detected in hematopoietic cells. Therefore, our data demonstrating genetic and functional correction of mbeta(c)(-/-) 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 beta(c)-deficient PAP.

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