News on GS-101 (Aganirsen)

Corneal Neovascularisation in Graft Patients

Corneal transplantation, or replacement of a patient’s damaged cornea with that of a donor cornea (graft), has a relatively high success rate. This is attributable to the privileged “immune status” of the cornea, which reduces rejection episodes common in other organ transplant situations. However, when sickly and leaky blood vessels invade the cornea – a condition known as pathologic corneal neovascularisation (CNV) - the situation changes, and the risk of graft rejection is again much higher. This is because the unwanted pathological vessels reduce the cornea’s privileged immune status. In fact, a recent meta-analysis confirmed the association between presence of pathological corneal neovessels and increased risk of graft rejection.

Consequently, and because of the long graft waiting lists that patients are faced with both in Europe and in the USA, it is desirable to apply a therapy such as aganirsen to reduce corneal neovascularisation and hence the risk of graft rejection. In Europe alone, there are an estimated 20,500 patients suffering from CNV.

Stromal Neovascularisation and Corneal Graft Rejection (CGR)

An avascular recipient cornea is commonly regarded as an important prognostic factor for long-term survival of a corneal graft.1 Cornea avascularity is essential not only for corneal transparency and vision, but also for granting immune-privilege to the cornea to protect  the donor cornea from being rejected.2

Corneal graft rejection is primarily a cell-mediated immune response controlled by T cells.3 Normal corneal immune privilege can be eroded by neovascularisation, especially if accompanied by the sequelae of ocular inflammation and raised intraocular pressure. This is because if neovascularisation is present either before or after a corneal graft, the growth of new blood vessels (angiogenesis) provides a route of entry for immune-mediating cells to the graft, while the growth of new lymphatic vessels enables the exit of APCs and antigenic material from the graft to regional lymph nodes. The cornea consequently becomes infiltrated with and sensitized to immune reaction mediators (i.e. APCs, T cells, macrophages, neutrophils). Therefore, although not an immune reaction in itself neovascularisation induces an immune response that can lead to immunological corneal graft rejection.4,5

Aganirsen GS-101 for the treatment of Neovascularisation in Graft patients 

GS-101 is an antisense oligonucleotide administered in the form of eye drops. It acts by blocking the production of the IRS-1, a protein required for the formation and growth of new blood vessels. By blocking the expression of IRS-1 in pro-angiogenic conditions, GS-101 inhibits and regresses corneal neovascularisation. It is well documented that the risk of a corneal graft rejection rises by two-thirds from a vascular eye to a highly neovascularised one.6

Clinical Progress in Corneal Neovascularisation

Gene Signal announced in May 2014 positive data from its I-CAN Phase III trial of aganirsen eye drops for corneal neovascularisation, a rare eye disease with European Orphan Drug designation. Published in the journal Ophthalmology
The I-CAN study was the first randomised trial of a topical inhibitor of corneal angiogenesis. It showed that topical applications of aganirsen are safe and well-tolerated, that it significantly reduces the relative area of corneal neovascularisation, and that the need for corneal transplantation is reduced in patients suffering from viral keratitis and central neovascularization

About neovascularisation and Corneal Grafts

 The following Orphan Drug designations were granted to Gene Signal for GS 101 - antisense oligonucleotide:

On October 2nd 2003, Orphan designation (EU/3/03/161) was granted by the European Commission to Gene Signal for GS-101 for the treatment of Neovascular Glaucoma

On October 2nd 2003, Orphan designation (EU/3/03/160) was granted by the European Commission to Gene Signal for GS-101 for the treatment of Retinopathy of Prematurity

On 17 April 2007, Orphan designation (EU/3/07/445) was granted by the European Commission to Gene Signal for GS-101 for the prevention of Corneal Graft Rejection