Gene Therapy of ßc-Deficient Pulmonary Alveolar Proteinosis (ßc-PAP): Studies in a Murine in vivo Model.

ABSTRACT

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