Treatment for Age-related Macular Degeneration
Image credit: https://irisvision.com/age-related-macular-degeneration/
By Shubhankar Kulkarni on Jul 30, 2020
Question: Novel treatment approaches needed for Age-related Macular Degeneration.
Age-related Macular Degeneration (AMD) is the leading cause of irreversible vision loss among elderly people. Although the underlying cause of the development of AMD is not known, wet AMD is treated with antibodies against vascular endothelial growth factor (VEGF). (This leads us to another question discussed here). And currently, there is no treatment for dry AMD (although some are at the clinical stage).
When the lysosomal endonuclease Dnase2a (that degrades DNA fragments) was deleted, there was cytosolic accumulation of nuclear-DNA (nDNA) in RPE (retinal pigment epithelium) cells. The cells subsequently became senescent and secreted higher levels of VEGF and pro-inflammatory cytokines. These effects were mediated by the DNA sensor STING and mTOR pathway. Similar to other senescent cells, these senescent RPE cells secreted factors that acted in a paracrine manner and initiated senescence in neighboring healthy cells. These newly turned cells also started secreting VEGF as well as pro-inflammatory cytokines.
In light of these recent findings, in what way can we modify the existing treatment for AMD?
 Haijiang Lin, Bo Tian, Ahmad Al Moujahed, Joan W Miller, Demetrios G. Vavvas; Accumulation of damaged nDNA promotes RPE cellular senescence and pro-inflammation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5235.
Promising new treatments for AMD
Here is a list of some AMD treatments that are on the horizon https://www.aao.org/eye-health/tips-prevention/promising-new-treatments-amd
by Darko Savic on Jul 30, 2020
Using Senolytics to Treat AMD
As already mentioned, age-related macular degeneration (AMD) is characterised by a marked increase in senescent cells and the senescence-associated secretory phenotype (SASP). (https://www.sciencedirect.com/science/article/abs/pii/S0306987712000291?via%3Dihub) Therefore, the usage of senolytics or senostatics to remove senescent cells or SASP respectively could be used as a novel treatment for AMD. Previous studies have shown that clearing senescent cells with senolytics can alleviate the symptoms of age-related diseases such as osteoarthritis, cardiovascular disease, renal disease and much more. (https://www.sciencedirect.com/science/article/abs/pii/S1931524420301468) Furthermore, the usage of senolytics such as the combination of dasatinib and quercetin has been associated with an improved lifespan in aged rats (https://pubmed.ncbi.nlm.nih.gov/29988130/) Quercetin is a naturally occurring flavonoid found in many fruits and vegetables. Quercetin has strong antioxidant properties but a low bioavailability, unfortunately. In a study, the solid dispersion of quercetin phospholipid complex (Q-SD) was prepared and used in a mouse model of dry AMD. It was found that Q-SD had an improved bioavailability compared to quercetin standalone. Furthermore, Q-SD had improved protective effects against retinal oxidative injury in the dry AMD model and these protective effects were related to enhanced Nrf2 signalling. (https://www.hindawi.com/journals/omcl/2019/1479571/) Therefore, various senolytics should be further researched as a treatment for AMD.
by Jamila Ahmed on Aug 03, 2020
Retinal Pigment Epithelium Replacement Therapy
Transplantation of healthy Retinal Pigment Epithelium (RPE) into patients with AMD may prevent further disease progression and may improve vision. The aim of RPE therapy is to replenish the RPE that is lost due to AMD and to protect the remaining photoreceptors from further damage. (https://www.annualreviews.org/doi/abs/10.1146/annurev-pharmtox-010919-023245) In a study by Sharma, an RPE injury was generated in pigs and then an iPSC-RPE patch was administered into a pig model. Sharma and colleagues found that the iPSC-RPE patch adjusted to the eyes prior to 10 weeks, the death of overlying photoreceptors was suppressed, and the phagocytosis of photoreceptor outer segments was enhanced. (https://stm.sciencemag.org/content/11/475/eaat5580.full) In June, the interim results for a clinical study conducted by Riemann were released. In the phase I/IIa clinical trial, healthy RPE was transplanted into human patients with dry AMD. It was found that RPE therapy was tolerated well by the patients and there were no adverse effects reported. Interestingly, there were changes in the appearance of the eyes, the characteristic drusen appearance seen in AMD patients was altered. (https://iovs.arvojournals.org/article.aspx?articleid=2766771) This research suggests that RPE transplants may have the potential to be a therapeutic option for AMD patients in the future.
by Jamila Ahmed on Aug 04, 2020