Optimizing autologous cell grafts to improve stem cell gene therapy.
Over the past decade, stem cell gene therapy has achieved unprecedented curative outcomes for several genetic disorders. Despite the unequivocal success, clinical gene therapy still faces challenges. Genetically engineered hematopoietic stem cells are particularly vulnerable to attenuation of their repopulating capacity once exposed to culture conditions, ultimately leading to low engraftment levels posttransplant. This becomes of particular importance when transduction rates are low or/and competitive transplant conditions are generated by reduced-intensity conditioning in the absence of a selective advantage of the transduced over the unmodified cells. These limitations could partially be overcome by introducing megadoses of genetically modified CD34(+) cells into conditioned patients or by transplanting hematopoietic stem cells hematopoietic stem cells with high engrafting and repopulating potential. On the basis of the lessons gained from cord blood transplantation, we summarize the most promising approaches to date of increasing either the numbers of hematopoietic stem cells for transplantation or/and their engraftability, as a platform toward the optimization of engineered stem cell grafts.
Gene and Cell Therapy Center, Hematology Department-BMT Unit, George Papanicolaou Hospital, Thessaloniki, Greece; Department of Medicine, University of Washington, Seattle, WA.
Nikoletta
N
Psatha
Gene and Cell Therapy Center, Hematology Department-BMT Unit, George Papanicolaou Hospital, Thessaloniki, Greece.
Garyfalia
G
Karponi
Gene and Cell Therapy Center, Hematology Department-BMT Unit, George Papanicolaou Hospital, Thessaloniki, Greece; Department of Medicine, University of Washington, Seattle, WA. Electronic address: eyannaki@u.washington.edu.
Evangelia
E
Yannaki
D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods / Q000592:standards; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction; D033581:Stem Cell Transplantation / Q000379:methods / Q000592:standards; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014161:Transduction, Genetic; D014182:Transplantation, Autologous