Dv. Lejnieks et al., GRANULOCYTE-COLONY-STIMULATING FACTOR EXPRESSION FROM TRANSDUCED VASCULAR SMOOTH-MUSCLE CELLS PROVIDES SUSTAINED NEUTROPHIL INCREASES IN RATS, Human gene therapy, 7(12), 1996, pp. 1431-1436
Granulocyte colony-stimulating factor (G-CSF) regulates granulocyte pr
ecursor cell proliferation, neutrophil survival, and activation. Cycli
c hematopoiesis, a disease that occurs both in humans and grey collie
dogs is characterized by cyclical variations in blood neutrophils. Alt
hough the underlying molecular defect is not known, long-term daily ad
ministration of recombinant G-CSF eliminates the severe recurrent neut
ropenia, indicating that expression of G-CSF by gene therapy would be
beneficial. As a prelude to preclinical studies in affected collie dog
s, we monitored hematopoiesis in rats receiving vascular smooth muscle
cells transduced to express G-CSF. Cells transduced with LrGSN, a ret
rovirus expressing rat G-CSF, were implanted in the carotid artery and
control animals received cells transduced with LASN, a retrovirus exp
ressing human adenosine deaminase (ADA). Test animals showed significa
nt increases in neutrophil counts for at least 7 weeks, with mean valu
es of 3,670 +/- 740 cells/mu l in comparison to 1,870 +/- 460 cells/mu
l in controls (p < 0.001). Thus, in rats G-CSF gene transfer targeted
at vascular smooth muscle cells initiated sustained production of 1,8
00 neutrophils/mu l, 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 th
at retrovirally transduced vascular smooth muscle cells can provide su
stained clinically useful levels of neutrophils in vivo.