Aganirsen
Aganirsen is a 25-mer DNA antisense oligonucleotide therapeutic inhibiting insulin receptor substrate-1, which is being investigated as a topical treatment for ocular neovascularization. Aganirsen is a candidate for the treatment of ocular neovascularization in patients with front of the eye or back of the eye diseases, including progressive corneal neovascularization in patients with infectious keratitis and wet age related macular degeneration.
Aganirsen actively inhibits the production of IRS-1 by binding IRS-1 mRNA. Aganirsen therefore induces an upstream inhibition of the neovascularization pathway, most notably by inhibiting excess VEGF and interleukin-1β expression.
Structure
Aganirsen is a 25-mer first-generation antisense oligonucleotide with the following sequence:- 5'-TAT CCG GAG GGC TCG CCA TGC TGC T-3'
Mechanism of action
IRS-1 is an intracellular docking protein deprived of enzymatic activity. IRS-1 is overexpressed in endothelial cells under neovascularization conditions. IRS-1 has been suggested as a target for the regulation of angiogenesis mediated by hypoxia, insulin and inflammation.IRS-1's main function is to act as a signal transmitter for intracellular pathways. IRS-1mainly interacts with the angiogenesis pathway by interacting with the VEGF-receptor complex. Aganirsen therefore reduces angiogenesis by inhibiting VEGF and inflammatory cytokines production upstream by specifically targeting IRS-1 mRNA.
Clinical development
The drug was discovered by S. Al-Mahmood, in Paris, France and then developed to Phase III in progressive corneal neovascularisation in patients with infectious keratitis and on the waiting list for Corneal Graft replacement. The dose-dependent effect of topical Aganirsen on Choroidal Neovascularization has also been evaluated in a non-human primate laser-induced model of wet-AMD. Aganirsen has also been investigated in Psoriasis, where it was found that lesion size reduction was associated with reduced expression of IRS-1, TNFα, and vascular endothelial growth factor.In April 2007, the EMA's Committee for Orphan Medicinal Products granted Gene Signal orphan designation for aganirsen for the prevention of corneal graft rejection associated with excessive neovascularisation of the host cornea. In April 2014, the EMA also granted Aganirsen an Orphan drug designation for ischemic Central retinal vein Occlusion. A randomised, double-masked, 3-group, placebo-controlled trial has received European Health Directorate funding to assess the drug's efficacy in reducing the rate of anterior and posterior segment neovascularisation and Neovascular Glaucoma development after ischemic CRVO.