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(American Journal of Pathology. 1999;154:169-179.)
© 1999 American Society for Investigative Pathology

Regular Articles

Novel Approach to Specific Growth Factor Inhibition in Vivo

Antagonism of Platelet-Derived Growth Factor inGlomerulonephritis by Aptamers

Jürgen Floege* , Tammo Ostendorf* , Ulf Janssen* , Michael Burg* , Heinfried H. Radeke{dagger} , Chandra Vargeese{ddagger} , Stanley C. Gill{ddagger} , Louis S. Green{ddagger} and Nebojsa Janjic{ddagger}

From the Divisions of Nephrology* and Clinical Pharmacology,{dagger} Medizinische Hochschule, Hannover, Germany, and NeXstar Pharmaceuticals,{ddagger} Boulder, Colorado

Mesangial cell proliferation and matrix accumulation, driven by platelet-derived growth factor (PDGF), contribute to many progressive renal diseases. In a novel approach to antagonize PDGF, we investigated the effects of a nuclease-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 glomerulonephritis model. Twice-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 endogenous PDGF B-chain, 4) reduced glomerular monocyte/macrophage influx on day 6 after disease induction, and 5) a marked reduction of glomerular extracellular matrix overproduction (as assessed by analysis of fibronectin and type IV collagen) both on the protein and mRNA level. The administration of equivalent 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.




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