Potential of 6-Aza-Indazole as a Renewable Therapy to Treat Diabetic Retinopathy through Inhibition of Factor D Complement

Dhitta Shabrina, Ihya Fakrurizal, Afid Brilliana P

Abstract


Diabetes mellitus is a chronic disease that has a high prevalence in Indonesia. One of diabetes’ complications is Diabetic Retinopathy (DR). DR is one of the highest cause of preventable blindness in the world. The treatment for DR up till then uses intravitreal anti-VEGF injection, intravitreal steroid antiinflammation injection. Intravitreal administration can cause some side effects such as increased intraocular pressure and endophthalmitis. Furthermore, patient’s convenience is also disturbed, for always having to see a medical personnel frequently. One pathogenesis of DR is the activation of the complement system which causes lysis of endothelial cells and results in ischemic damage to the retina. This ischemic effect will stimulate VEGF secretion that manifests in the phase of Proliferative Diabetic Retinopathy (PDR). Inhibitor of D factor, 6-aza indazole is a small size protein, less than 300 Da which has the potential to inhibit progress of DR by interfering with the activation of alternative pathway (AP) of the complement system. This is supported by the in-vivo test result, where there is a significant inhibition of intraocular AP activation continuously for 8 hours after an oral administration of this agent at a dose of 30 mg/kg. But this study is still in a pre-clinical phase that uses mice as the subject. Therefore, there must be a further study and clinical trial to find out the dosage and safety of this agent to be applied to humans.

 

Keywords: 6-aza indazole, alternative pathway, complement factor D inhibitor, diabetic retinopathy


Full Text:

PDF

References


Kementerian Kesehatan RI Pusat Data dan Informasi. Situasi dan Analisis Diabetes. Jakarta: Kemenkes RI; 2014. p. 1-8

Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye and Vision [Internet]. 2015 Sep 30;2(1). Available from: http://dx.doi.org/10.1186/s40662-015- 0026-2

World Health Organization, Blindness and Vision Impairment Prevention. Jeneva: WHO; 2019. Available from : https://www.who.int/blindness/causes/prio rity/en/index5.html

Wang W, Lo A. Diabetic Retinopathy: Pathophysiology and Treatments. Int J Mol Sci [Internet]. 2018 Jun 20;19(6):1816. Available from: http://dx.doi.org/10.3390/ijms19061816

Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet [Internet]. 2010;376(9735):124–36. Available from: http://www.sciencedirect.com/science/arti cle/pii/S0140673609621243

Altomare F, Kherani A, Lovshin J. Retinopathy. Can J Diabetes [Internet]. 2018;42:S210–6. Available from: http://www.sciencedirect.com/science/arti cle/pii/S1499267117308377

Tsai T, Kuehn S, Tsiampalis N, Vu M-K, Kakkassery V, Stute G, et al. Anti-inflammatory cytokine and angiogenic factors levels in vitreous samples of diabetic retinopathy patients. PLoS One [Internet]. 2018;13(3):1–13. Available from: https://doi.org/10.1371/journal.pone.01946 03

Manoharan N, Patnaik JL, Olson JL. Increased complement levels in human vitreous aspirates of proliferative diabetic retinopathy and retinal detachment eyes. Retina [Internet]. 2018 Aug;1. Available from: http://dx.doi.org/10.1097/IAE.0000000000 002288

Rübsam A, Parikh S, Fort PE. Role of inflammation in diabetic retinopathy. Int J Mol Sci [Internet]. 2018;19(4). Available from: http://www.mdpi.com/1422- 0067/19/4/942

Stanton CM, Yates JRW, den Hollander AI, Seddon JM, Swaroop A, Stambolian D, et al. Complement factor d in age-related macular degeneration. Invest Ophthalmol Vis Sci [Internet]. 2011 Nov 11;52(12):8828–34. Available from: https://doi.org/10.1167/iovs.11-7933

Thurman JM, Renner B, Kunchithapautham K, Ferreira VP, Pangburn MK, Ablonczy Z, et al. Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem [Internet].2009 Jun 19;284(25):16939–47. Available from: http://www.jbc.org/content/284/25/16939. abstract

Lu L, Jiang Y, Jaganathan R, Hao Y. Current Advances in Pharmacotherapy and Technology for Diabetic Retinopathy: A Systematic Review. Journal of Ophthalmology [Internet]. 2018;2018:1– 13. Available from: http://dx.doi.org/10.1155/2018/1694187

Miller K, Fortun JA. Diabetic Macular Edema: Current Understanding, Pharmacologic Treatment Options, and Developing Therapies. Asia-Pacific Journal of Ophthalmology [Internet]. 2018;7(1). Available from: http://dx.doi.org/10.22608/apo.2017529

Maibaum J, Liao S-M, Vulpetti A, Ostermann N, Randl S, Rüdisser S, et al. Small-molecule factor D inhibitors targeting the alternative complement pathway. Nature Chemical Biology [Internet]. 2016 Oct 24;12(12):1105–10. Available from: http://dx.doi.org/10.1038/nCHeMBIO.220 8

Loyet KM, Good J, Davancaze T, Sturgeon L, Wang X, Yang J, et al. Complement Inhibition in Cynomolgus Monkeys by Anti-Factor D Antigen- Binding Fragment for the Treatment of an Advanced Form of Dry Age-Related Macular Degeneration. J Pharmacol Exp Ther [Internet]. 2014 Sep 17;351(3):527– 37. Available from: http://dx.doi.org/10.1124/jpet.114.215921




DOI: https://doi.org/10.26618/aimj.v3i1.2747

Refbacks

  • There are currently no refbacks.


Copyright (c) 2019 Dhitta Shabrina, Ihya Fakrurizal, Afid Brilliana P

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Flag Counter