In vivo selection using a cell-growth switch

A major obstacle to stem-cell gene therapy rests in the inability to delive r a gene into a therapeutically relevant fraction of stem cells'. One way t o circumvent this obstacle is to use selection. Vectors containing two link ed genes serve as the basis for selection. with one gene encoding a selecta ble product and the other, a therapeutic protein. Applying selection in viv o has the potential to bring a minor population of genetically corrected ce lls into the therapeutic range. But strategies for achieving in vivo select ion have traditionally relied on genes that confer resistance to cytotoxic drugs(2,3) and are encumbered by toxicity. Here we describe a new system fo r in vivo selection that uses a 'cell-growth switch'. allowing a minor popu lation of genetically modified cells to be inducibly amplified, thereby ave rting the risks associated with cytotoxic drugs. This system provides a gen eral platform for conditionally expanding genetically modified cell populat ions in vivo. and may have widespread applications in gene and cell therapy .