title: In vivo selection using a cell-growth switch.
abstract: A major obstacle to stem-cell gene therapy rests in the inability to deliver a gene into a therapeutically relevant fraction of stem cells. One way to circumvent this obstacle is to use selection. Vectors containing two linked genes serve as the basis for selection, with one gene encoding a selectable product and the other, a therapeutic protein. Applying selection in vivo has the potential to bring a minor population of genetically corrected cells into the therapeutic range. But strategies for achieving in vivo selection have traditionally relied on genes that confer resistance to cytotoxic drugs and are encumbered by toxicity. Here we describe a new system for in vivo selection that uses a 'cell-growth switch', allowing a minor population of genetically corrected cells into the therapeutic range. But strategies for achieving in vivo selection have traditionally relied on genes that confer resistance to cytotoxic drugs and are encumbered by toxicity. Here we describe a new system for in vivo selection that uses a 'cell-growth switch', allowing a minor population of genetically modified cells to be inducibly amplified, thereby averting the risks associated with cytotoxic drugs. This system provides a general platform for conditionally expanding genetically modified cell populations in vivo, and may have widespread applications in gene and cell therapy.
authors.affiliation: Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: H
authors.initials: H
authors.lastname: Zeng
authors.forename: S
authors.initials: S
authors.lastname: Chien
authors.forename: K G
authors.initials: KG
authors.lastname: Otto
authors.forename: R E
authors.initials: RE
authors.lastname: Richard
authors.forename: D W
authors.initials: DW
authors.lastname: Emery
authors.forename: C A
authors.initials: CA
authors.lastname: Blau
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism; D015139:Blotting, Southern; D016026:Bone Marrow Transplantation; D018929:Cell Culture Techniques / Q000379:methods; D002469:Cell Separation; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D049452:Green Fluorescent Proteins; D007700:Kinetics; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D009363:Neoplasm Proteins; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin / Q000737:chemistry / Q000378:metabolism; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D019076:Transgenes
chemical_list: D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin; D053628:Receptors, Thrombopoietin; D011993:Recombinant Fusion Proteins; C082218:MPL protein, human; D049452:Green Fluorescent Proteins; D019009:Proto-Oncogene Proteins c-kit