Antisense oligonucleotide therapy in diabetic retinopathy

Abstract

Diabetic retinopathy is one of the leading causes of blindness in the United States and other parts of the world. Historically, laser photocoagulation and vitrectomy surgery have been used for the treatment of diabetic retinopathy, including diabetic macular edema. Both procedures have proven to be useful under certain conditions but have their limitations. New pathways and processes that promote diabetic retinopathy have been identified, and several new therapeutic approaches are under investigation. These new therapies may be beneficial in the treatment of diabetic retinopathy and include antivascular endothelial growth factor agents, corticosteroids, and therapies that may potentially target a number of additional diabetic retinopathy-related factors and processes, including antisense oligonucleotides. Second-generation antisense oligonucleotides, such as iCo-007, may offer a significant advantage in the treatment of diabetic retinopathy by downregulating the signal pathways of multiple growth factors that seem to play a critical role in the process of ocular angiogenesis and vascular leakage. Benefits of such molecules are expected to include the specificity of the kinase target and an extended half-life, resulting in less frequent intravitreal drug administration, resistance to molecule degradation, and a good safety profile.

Figure 1.

Fluorescein angiogram (midphase) demonstrating multiple retinal microaneurysms in a nonproliferative DR.

Figure 2.

Fundus photography demonstrating proliferative diabetic retinopathy with preretinal hemorrhage and slight new vessel development.

Figure 3.

Wide-field Optos photograph demonstrating proliferative retinopathy with fibroglial changes and early tractional retinal detachment.

Figure 4.

A simplified view of the antisense mechanism. The single-stranded antisense oligonucleotide enters the cell and interacts with its specific target mRNA in the cytoplasm or nucleus. There, it recruits RNase H, which cleaves the mRNA target in the mRNA–DNA duplex. Thus, the message in the mRNA is intercepted and no longer readable.