J. Floege et al., Novel approach to specific growth factor inhibition in vivo - Antagonism of platelet-derived growth factor in glomerulonephritis by aptamers, AM J PATH, 154(1), 1999, pp. 169-179
Citations number
36
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Mesangial cell proliferation and matrix accumulation, driven by platelet-de
rived growth factor (PDGF), contribute to many progressive renal diseases.
In a novel approach to antagonize PDGF, we investigated the effects of a nu
clease-resistant high-affinity oligonucleotide aptamer in vitro and in vivo
. In cultured mesangial cells, the aptamer markedly suppressed PDGF-BB but
not epidermal- or fibroblast-growth-factor-2-induced proliferation, In vivo
effects of the aptamer were evaluated in a rat mesangioproliferative glome
rulonephritis model, Tn ice-daily intravenous (i,v,) injections from days 3
to 8 after disease induction of 2.2 mg/kg PDGF-B aptamer, coupled to 40-kd
polyethylene glycol (PEG), led to 1) a reduction of glomerular mitoses by
64% on day 6 and by 78% on day 9, 2) a reduction of proliferating mesangial
cells by 95% on day 9, 3) markedly reduced glomerular expression of endoge
nous PDGF B-chain, 4) reduced glomerular monocyte/macrophage influx on day
6 after disease induction, and 5) a marked reduction of glomerular extracel
lular matrix overproduction las assessed by analysis of fibronectin and typ
e TV collagen) both on the protein and mRNA level. The administration of eq
uivalent amounts of a PEG-coupled aptamer with a scrambled sequence or PEG
alone had no beneficial effect on the natural course of the disease, These
data show that specific inhibition of growth factors using custom-designed,
high-affinity aptamers is feasible and effective.