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

Published Online: May 22nd 2012 European Ophthalmic Review, 2012;6(3):190 –3 DOI: http://doi.org/10.17925/EOR.2012.06.03.190
Authors: James W Bainbridge, Vanya Loroch, Eric Viaud, Claus Cursiefen
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Abstract:
Overview

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.

Keywords

Aganirsen (GS-101), antisense oligonucleotide, insulin receptor substrate-1, ocular disorders, topical anti-angiogenic therapy, adjunct to anti-VEGF, healthy and pathological angiogenesis

Article:

Angiogenesis and its Importance in Health and Disease
The formation of new blood vessels, commonly called ‘angiogenesis’, comprises several processes that include vasculogenesis, where stem cells or angioblasts differentiate into blood vessels and which occurs in developing, initially avascular embryos and to a certain extent in adults;1 and angiogenesis per se, where new blood vessels (especially capillaries) grow from pre-existing vessels by sprouting or branching2 and which is the prevailing mechanism in adults.3

Angiogenesis is necessary to supply tissues with nutrients and oxygen, and is an integral mechanism in many physiological processes, such as wound healing and tissue growth and repair,4 muscle development5 and ovulation.6 At the same time, disruption of the fine balance between factors that induce blood vessel formation and those that inhibit or halt the process can result in pathological angiogenesis, or neovascularisation, leading to increased formation of blood vessels that may be excessive or occur in normally avascular tissue. For example, rapid and persistent growth of new blood vessels is a hallmark of cancer, while excessive angiogenesis can provide a route of entry for inflammatory cells into sites of chronic injury (e.g. Crohn’s disease), contributes to the increased epithelial cell turnover and skin plaques in psoriasis and causes ocular diseases that can lead to blindess.7 Neovascularisation is implicated in a multitude of malignant, ischaemic, inflammatory, infectious and immune disorders.3

As angiogenesis is so vital for health, any therapeutic strategy aimed at treating angiogenic-mediated disease must discriminate between physiological and pathological angiogenesis to ensure that only neovascularisation is affected. It is also important to recognise that all angiogenic mechanisms may participate in neovascularisation to various extents in different diseases. A thorough understanding of the processes controlling angiogenesis and gaining access to as many molecular targets in the relevant regulatory pathways as possible is essential in developing an appropriate therapy.

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Disclosure

James W Bainbridge is a NIHR Research Professor and is supported by the NIHR Biomedical Research Centre for Ophthalmology at Moorfields and UCL. He has participated in one clinical trial workshop sponsored by Gene Signal. Claus Cursiefen and Vanya Loroch are consultants to Gene Signal. Eric Viaud is the Chief Executive Officer of Gene Signal International SA.

Correspondence

Claus Cursiefen, University of Cologne, Albertus-Magnus-Platz 1, 50931 Cologne, Germany. E: claus.cursiefen@uk-koeln.de

Support

The publication of this article was funded by Gene Signal.

Received

2012-06-15T00:00:00

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