Gene therapy of beta(c)-deficient pulmonary alveolar proteinosis (beta(c)-PAP): studies in a murine in vivo model

Mol Ther. 2008 Apr;16(4):757-64. doi: 10.1038/mt.2008.7. Epub 2008 Mar 4.


Pulmonary 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Bone Marrow Transplantation
  • Cells, Cultured
  • Colony-Forming Units Assay
  • Cytokine Receptor Common beta Subunit / biosynthesis*
  • Cytokine Receptor Common beta Subunit / genetics
  • Genetic Therapy
  • Granulocyte-Macrophage Colony-Stimulating Factor / drug effects
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Alveolar Proteinosis / metabolism
  • Pulmonary Alveolar Proteinosis / pathology
  • Pulmonary Alveolar Proteinosis / therapy*
  • Pulmonary Surfactants / metabolism
  • Retroviridae / genetics


  • Cytokine Receptor Common beta Subunit
  • Pulmonary Surfactants
  • Granulocyte-Macrophage Colony-Stimulating Factor