Many metabolic pathways, including oxidative stress, PKC and the
polyol pathway have been implicated in the development of
diabetic retinopathy, but despite extensive research, its pathogenesis remains unclear. Recent studies have shown the role of a low-molecular-weight
GTP-binding protein (H-Ras)-mediated signaling pathway in its development. The key effector
protein of Ras function is a
threonine/
serine kinase-
Raf kinase, and this
kinase is involved in a variety of functions, including the cell cycle and proliferation and apoptosis. In animal models of
diabetic retinopathy,
Raf kinase is activated in the retina and its microvasculature. Activated
Raf kinase is associated with increased apoptosis of
retinal capillary cells, the process that precedes the development of
retinal histopathology, and inhibition of
Raf kinase ameliorates apoptosis. In clinical settings, inhibitors of
Raf kinase have shown promising results in
cancer treatment, and
Raf kinase antisense oligonucleotides, iCo 007, is now in Phase II trial for
macular edema, a chronic ocular disease associated with
retinal neovascularization. Further elucidating the role of
Raf kinase in
diabetic retinopathy, and advances in the generation of antisense
therapy for
chronic diseases, should help test Raf
antisense oligonucleotides for the treatment of this blinding complication that diabetic patients fear the most.