Gene therapy of βc-deficient pulmonary alveolar proteinosis (βc- PAP):: Studies in a murine in vivo model

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 (GMCSF) 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 (m beta c) gene and conducted investigations in a murine model of beta c-deficient PAP. Functional correction of m beta c activity in m beta 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 m beta c-deficient PAP m beta 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 m beta 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.