Granulocyte colony-stimulating factor expression from transduced vascular smooth muscle cells provides sustained neutrophil increases in rats.
Granulocyte colony-stimulating factor (G-CSF) regulates granulocyte precursor cell proliferation, neutrophil survival, and activation. Cyclic hematopoiesis, a disease that occurs both in humans and grey collie dogs is characterized by cyclical variations in blood neutrophils. Although the underlying molecular defect is not known, long-term daily administration of recombinant G-CSF eliminates the severe recurrent neutropenia, indicating that expression of G-CSF by gene therapy would be beneficial. As a prelude to preclinical studies in affected collie dogs, we monitored hematopoiesis in rats receiving vascular smooth muscle cells transduced to express G-CSF. Cells transduced with LrGSN, a retrovirus expressing rat G-CSF, were implanted in the carotid artery and control animals received cells transduced with LASN, a retrovirus expressing human adenosine deaminase (ADA). Test animals showed significant increases in neutrophil counts for at least 7 weeks, with mean values of 3,670 +/- 740 cells/microliter in comparison to 1,870 +/- 460 cells/microliter in controls (p < 0.001). Thus, in rats G-CSF gene transfer targeted at vascular smooth muscle cells initiated sustained production of 1,800 neutrophils/microliter, a cell number that would provide clinical benefit to patients. Lymphocytes, red cells and platelets were not different between control and test animals (p > 0.05). These studies indicate that retrovirally transduced vascular smooth muscle cells can provide sustained clinically useful levels of neutrophils in vivo.
Lejnieks
D V
DV
Department of Pediatrics, University of Washington, Seattle 98195, USA.
Han
S W
SW
Ramesh
N
N
Lau
S
S
Osborne
W R
WR
D000243:Adenosine Deaminase / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000166:cytology; D002339:Carotid Arteries; D017690:Cell Transplantation; D002478:Cells, Cultured / Q000637:transplantation; D004285:Dogs; D005822:Genetic Vectors / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis*
D011993:Recombinant Fusion Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000243:Adenosine Deaminase