Aganirsen
Aganirsen (previously GS-101) is a 25 mer DNA antisense oligonucleotide therapeutic inhibiting insulin receptor substrate-1 (IRS-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 (cornea) or back of the eye (retinal) diseases, including progressive corneal neovascularization in patients with infectious keratitis and wet age related macular degeneration (AMD).
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all-P-ambo-thymidylyl-(3′→5′)-2′-deoxy-P-thioadenylyl-(3′→5′)-P- thiothymidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P- thiocytidylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxy-P- thioguanylyl-(3′→5′)-2′-deoxy-P-thioadenylyl-(3′→5′)-2′-deoxy-P- thioguanylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxy-P- thioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-P- thiothymidylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P- thioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-2′-deoxy-P- thiocytidylyl-(3′→5′)-2′-deoxy-P-thioadenylyl-(3′→5′)-P- thiothymidylyl-(3′→5′)-2′-deoxy-P-thioguanylyl-(3′→5′)-2′-deoxy-P- thiocytidylyl-(3′→5′)-P-thiothymidylyl-(3′→5′)-2′-deoxy-P- thioguanylyl-(3′→5′)-2′-deoxy-P-thiocytidylyl-(3′→5′)-P-thiothymidine | |
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C242H307N91O127P24S24 |
| Molar mass | 8035.44 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Aganirsen actively inhibits the production of IRS-1 by binding IRS-1 mRNA (antisense therapy). Aganirsen therefore induces an upstream inhibition of the neovascularization pathway, most notably by inhibiting excess VEGF and Il-1β expression.
Structure
Aganirsen is a 25-mer (5'-TATCCGGAGGGCTCGCCATGCTGCT-3'), first-generation antisense oligonucleotide (phosphorothioate linkage). Aganirsen has a molecular mass of 8036 (Da), a melting point of approximately 64.2 °C, and a GC content of 64%. Aganirsen is highly soluble in water.
Mechanism of action
IRS-1 is an intracellular docking protein deprived of enzymatic activity.[1] IRS-1 is overexpressed in endothelial cells under neovascularization conditions.[2] IRS-1 has been suggested as a target for the regulation of angiogenesis mediated by hypoxia, insulin and inflammation.[3]
IRS-1's main function is to act as a signal transmitter for intracellular pathways.[4] 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.[5]
Clinical development
The drug was discovered by S. Al-Mahmood,[6] 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 (an EU Orphan Drug designation).[7][8][9] The dose-dependent effect of topical Aganirsen on Choroidal Neovascularization has also been evaluated in a non-human primate (NHP) laser-induced model of wet-AMD.[10] Aganirsen has also been investigated in Psoriasis, where it was found that lesion size reduction was associated with reduced expression of IRS-1 (P < 0.01), TNFα (P < 0.0001), and vascular endothelial growth factor (P < 0.01).[11]
In April 2007, the EMA's Committee for Orphan Medicinal Products (COMP) granted Gene Signal orphan designation for aganirsen for the prevention of corneal graft rejection associated with excessive neovascularisation of the host cornea (EMEA/COMP/108186/2007).[12] In April 2014, the EMA also granted Aganirsen an Orphan drug designation for ischemic Central retinal vein Occlusion (iCRVO).[13] A randomised, double-masked, 3-group, placebo-controlled trial (STRONG Study) has received European Health Directorate (FP-7) funding to assess the drug's efficacy in reducing the rate of anterior and posterior segment neovascularisation and Neovascular Glaucoma (NVG) development after ischemic CRVO.[14]
Delivery
Aganirsen is under investigation for topical delivery (eye drops and eye emulsion). Toxicology studies in rabbits and humans revealed that aganirsen was well tolerated independently of the concentration delivered.[15]
References
- Sun, Xiao Jian, "Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein." Nature 352, no. 6330 (1991): 73-77.
- Zhen Y. Jiang et al, "Characterization of Multiple Signaling Pathways of Insulin in the Regulation of Vascular Endothelial Growth Factor Expression in Vascular Cells and Angiogenesis", The Journal of Biological Chemistry, Vol. 278, No. 34, Issue of August 22, pp. 31964 –31971, 2003 (Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts)
- Andrieu-Soler C et al "Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis" Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4072-8
- THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 278, No. 34, Issue of August 22, pp. 31964–31971, 2003 THE AMERICAN SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY
- Salman Al-Mahmood, Sylvie Colin, Nada Farhat, Eric Thorin, Céline Steverlynck, and Sylvain Chemtob,Potent in Vivo Antiangiogenic Effects of GS-101 (5'- TATCCGGAGGGCTCGCCATGCTGCT-3'), an Antisense Oligonucleotide Preventing the Expression of Insulin Receptor Substrate-1, THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTIC, February 9, 2009
- Al-Mahmood Salman (2002), inventor; Gene Signal International SA, assignee. Antisense oligonucleotides which can inhibit the formation of capillary tubes by endothelial cells. U.S. patent US7417033
- Kein H.L. et al "Tolerability and safety of GS-101 eye drops, an antisense oligonucleotide to insulin receptor substrate-1: a first in man phase I investigation", British Journal of Clinical Pharmacology (BJCP), August 2009. Study performed at the University Eye Clinic (Augenklinik der Universität Basel), Department of Ophthalmology, Basel, Switzerland
- Claus Cursiefen et al, "GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularization: interim results of a randomized phase II trial" Ophthalmology 2009; 116: 1630-1638
- Cursiefen C. et al "Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study" Ophthalmology 2014
- Cloutier et al « Antiangiogenic activity of Aganirsen in primate and rodent models of retinal neovascular disease after topical administration: IOVS, March 2012, Vol. 53, No.3
- Colin S et al "The antiangiogenic insulin receptor substrate-1 antisense oligonucleotide aganirsen impairs AU-rich mRNA stability by reducing 14-3-3β-tristetraprolin protein complex, reducing inflammation and psoriatic lesion size in patients.J Pharmacol Exp Ther. 2014 Apr;349(1):107-17. doi: 10.1124/jpet.113.209346. Epub 2014 Feb 6
- http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2009/11/human_orphan_000451.jsp&mid=WC0b01ac058001d12b
- http://www.ema.europa.eu/docs/en_GB/document_library/Committee_meeting_report/2014/04/WC500165377.pdf
- Lorenz, K., The STRONG study. Acta Ophthalmologica 2012, 90: 0. doi: 10.1111/j.1755-3768.2012.2725.x
- Cloutier et al « Antiangiogenic activity of Aganirsen in primate and rodent models of retinal neovascular disease after topical administration: IOVS, March 2012, Vol. 53, No.3