Beyond Anti-VEGFs – Anti-Insulin Receptor Substrate-1 Oligonucleotides as a Novel Approach to Ocular Neovascular Disorders

Abstract

Angiogenesis is a complex process that is vital to health but is also a driving factor behind a broad range of malignant, ischaemic, inflammatory, infectious and immune disorders. For optimal efficacy and safety, therapies aimed at preventing angiogenic-mediated disorders must differentiate between healthy and pathological angiogenesis or neovascularisation. Aganirsen is an antisense oligonucleotide that inhibits the insulin receptor substrate (IRS)-1 angiogenic pathway by targeting the IRS-1 messenger RNA. To date, studies of aganirsen have focused mainly on ocular disorders because of the ability to assess non-invasively the effect of the drug on neovascularisation and to address the unmet need for effective therapies in these blinding disorders. Aganirsen (GS-101) eye drops inhibit progressive corneal neovascularisation and appear to be well tolerated. The drug may offer an alternative and/or adjunct to intraocular anti-vascular endothelial cell growth factor (VEGF) agents, which are the current reference standards to prevent neovascularisation in retinal diseases. This is because it has a different and potentially complementary mechanism of action and can be administered topically. Antisense oligonucleotides targeting IRS-1 may present a valuable new approach to control pathological angiogenesis in the eye and elsewhere.