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

Abstract

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.