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Wet AMD: treating the cause or the effect?

Image credit: http://advaitatoons.blogspot.com/2005/11/cause-and-effect-duality-illustrated.html

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Shubhankar Kulkarni
Shubhankar Kulkarni Jul 30, 2020
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Necessity

Is the problem still unsolved?

Conciseness

Is it concisely described?

In Age-related Macular Degeneration (AMD), cytosolic accumulation of nuclear-DNA (nDNA) is observed in the RPE (retinal pigment epithelium) cells. The cells subsequently become senescent and secrete higher levels of VEGF and pro-inflammatory cytokines. Although the underlying cause of the development of wet AMD is not known, it is treated with antibodies against vascular endothelial growth factor (VEGF).

From what we know, secretion of VEGF seems to be an effect rather than the cause of AMD. Moreover, the role of VEGF and other pro-inflammatory cytokines is to signal the body's defense and repair mechanisms and recruit them to the sight of the damage (in this case, the RPE cells). Therefore, using antibodies against VEGF to treat AMD seems akin to treating fever by creating a cold ambient environment. Increase in body temperature during fever is an effect and not the cause. No doubt reducing the symptoms (effects) of fever (or even AMD) will have certain positive effects. However, is it the right way to go or is it the only way out we have until we find a concrete target?
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Antiangiogenic & Alpha-lipoic Therapies

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Mohammad Shazaib
Mohammad Shazaib Oct 02, 2020
Treatment of the wet form of AMD had a significant breakthrough due to the advent of anti-angiogenic drugs; the functional prognosis unexpectedly improved from almost assured blindness to more than 90% of the chances of three-line visual improvement after two years of treatment. However, even with this development, therapy is far from ideal and there is still plenty of space for change.

Antiangiogenic therapy is intended to treat the effects of long-lasting cell damage but does not contribute much to the prevention and prophylaxis of the growth of AMD . In fact, this therapy does not alter the path of the disease at all, but simply resists its effect over time and slows down its progression. Furthermore, there is no established treatment available for the dry form of AMD .
This is partially because, until now, the findings of AMD studies have only started to unravel the complex relationship between genetic predisposition, environmental influences and the natural ageing phase that is taking place as part of the disease mechanisms. A deeper understanding of these relationships will allow us to define better future treatment goals for both wet and dry AMD.

Alpha-lipoic acid, which is a cofactor of mitochondrial dehydrogenase, is another choice for AMD treatment. It functions as a free radical scavenger, chelating transition metals, and facilitates the regeneration of endogenous antioxidant systems such as superoxide dismutase.

There are several factors that affect the origin and development of AMD and the more important mechanisms associated with chronic retinal degeneration. This opens new windows to include several therapeutic targets for the treatment of diseases . However, the design of new therapies needs to be performed very carefully because most of the altered pathways in AMD are essentially obsolete and may lead to harmful results.

[1]1. Velez-Montoya R., Oliver S. C. N., Olson J. L., Fine S. L., Mandava N., Quiroz-Mercado H. Current knowledge and trends in age-related macular degeneration: today’s and future treatments. Retina. 2013;33(8):1487–1502

[2]Salvi S. M., Akhtar S., Currie Z. Ageing changes in the eye. Postgraduate Medical Journal. 2006;82(971):581–587

[3]Ashraf M., Souka A. A. R. Aflibercept in age-related macular degeneration: evaluating its role as a primary therapeutic option. Eye. 2017;31(11):1523–1536

[4]Hahn P., Milam A. H., Dunaief J. L. Maculas affected by age-related macular degeneration contain increased chelatable iron in the retinal pigment epithelium and Bruch’s membrane. Archives of Ophthalmology. 2003;121(8):1099–1105

[5]Shaw P. X., Hörkkö S., Chang M. K., et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. The Journal of Clinical Investigation. 2000;105(12):1731–1740

[6] Hanus J., Zhao F., Wang S. Current therapeutic developments in atrophic age-related macular degeneration. British Journal of Ophthalmology. 2016;100(1):122–127

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