title: Gene therapy of beta(c)-deficient pulmonary alveolar proteinosis (beta(c)-PAP): studies in a murine in vivo model.
abstract: 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.
authors.affiliation: Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Essen, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Kleff
authors.forename: Ursula R
authors.initials: UR
authors.lastname: Sorg
authors.forename: Carsten
authors.initials: C
authors.lastname: Bury
authors.forename: Takuji
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ina
authors.initials: I
authors.lastname: Rattmann
authors.forename: Moran
authors.initials: M
authors.lastname: Jerabek-Willemsen
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.forename: Michael
authors.initials: M
authors.lastname: Flasshove
authors.forename: Bertram
authors.initials: B
authors.lastname: Opalka
authors.forename: Bruce
authors.initials: B
authors.lastname: Trapnell
authors.forename: Uta
authors.initials: U
authors.lastname: Dirksen
authors.forename: Thomas
authors.initials: T
authors.lastname: Moritz
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D053648:Cytokine Receptor Common beta Subunit / Q000096:biosynthesis* / Q000235:genetics; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011649:Pulmonary Alveolar Proteinosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011663:Pulmonary Surfactants / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics
chemical_list: D053648:Cytokine Receptor Common beta Subunit; D011663:Pulmonary Surfactants; D016178:Granulocyte-Macrophage Colony-Stimulating Factor