Pharmacologically regulated in vivo selection in a large animal.
The inefficiency of gene transfer has greatly hindered gene therapy. In vivo selection may increase the frequency of genetically modified cells, thereby circumventing this critical limitation. Here we demonstrate regulated in vivo selection in a large animal. CD34(+) cells from 2 dogs were engineered to express a conditional derivative of the thrombopoietin receptor (F36Vmpl). Activation of the receptor through administration of a dimerizing drug, AP20187, produced reversible, drug-dependent rises in genetically modified red cells, white cells, and platelets in both animals, with minimal side effects. Cell growth switches could greatly enhance the efficacy and applicability of gene and cell therapy.
Neff
Tobias
T
Divisions of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA 89195, USA.
Horn
Peter A
PA
Valli
Victor E
VE
Gown
Allen M
AM
Wardwell
Scott
S
Wood
Brent L
BL
von Kalle
Christof
C
Schmidt
Manfred
M
Peterson
Laura J
LJ
Morris
Julia C
JC
Richard
Robert E
RE
Clackson
Tim
T
Kiem
Hans-Peter
HP
Blau
C Anthony
CA
D000818:Animals; D018952:Antigens, CD34; D001772:Blood Cell Count; D004285:Dogs; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006085:Graft Survival / Q000187:drug effects*; D006410:Hematopoiesis / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D023421:Models, Animal; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D016559:Tacrolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D014161:Transduction, Genetic
C463061:AP20187; D018952:Antigens, CD34; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D016559:Tacrolimus