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Treatment for Age-related Macular Degeneration

Image credit: https://irisvision.com/age-related-macular-degeneration/

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Shubhankar Kulkarni
Shubhankar Kulkarni Jul 30, 2020

[1]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.

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Can we find some treatment cues from the complement system?

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Subash Chapagain
Subash Chapagain Nov 02, 2020

[1]Laufer J, Katz Y, Passwell JH . Extrahepatic synthesis of complement proteins in inflammation. Mol Immunol 2001

[2]Anderson DH, Mullins RF, Hageman GS, Johnson LV . A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002; 134 (3): 411–431.

[3]Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308 (5720): 385–389.

[4]Mullins RF, Schoo DP, Sohn EH, Flamme-Wiese MJ, Workamelahu G, Johnston RM, et al. The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol. (2014) 184:3142–53. doi: 10.1016/j.ajpath.2014.07.017

[5]Mullins RF, Aptsiauri N, Hageman GS . Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye 2001; 15 (Part 3): 390–395.

[6]Leung E, Landa G. Update on current and future novel therapies for dry age-related macular degeneration. Expert Rev Clin Pharmacol. 2013;6(5):565–579. doi:10.1586/17512433.2013.829645

[7]http://apellis.com/pdfs/Press%20Release%20FILLY%2012%20Month%20Results%20FINAL%20FINAL%20170823.pdf.

[8]Yehoshua Z, Filho CADAG, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology. 2014;121(3):693–701. doi:10.1016/j.ophtha.2013.09.044

[9]Mullins RF, Warwick AN, Sohn EH, Lotery AJ. From compliment to insult: genetics of the complement system in physiology and disease in the human retina. Hum Mol Genet. 2017;26(R1):R51–R57. doi:10.1093/hmg/ddx181

[10] Ricklin D, Mastellos DC, Reis ES, Lambris JD. The renaissance of complement therapeutics. Nat Rev Nephrol. 2018;14(1):26–47. doi:10.1038/nrneph.2017.156

[11]ClinicalTrials.gov. ZIMURA in combination with LUCENTIS in patients with Neovascular Age Related Macular Degeneration (NVAMD). 2017. NLM identifier: NCT03362190.

[12]Loyet KM, Good J, Davancaze T, 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. 2014;351(3):527–537. doi:10.1124/jpet.114.215921

[13]Volz C, Pauly D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur J Pharm Biopharm. 2015;95:158–172. doi:10.1016/j.ejpb.2015.02.020

[14]Wolf-Schnurrbusch UE, Stuck AK, Hess R, Wolf S, Enzmann V. Complement Factor P in choroidal neovascular membranes of patients with age-related macular degeneration. Retina. 2009;29(7):966–973. doi:10.1097/IAE.0b013e3181a2f40f

[15]Lesher A, Nilsson B, Song W-C. Properdin in complement activation and tissue injury. Mol Immunol. 2013;56(3):191–198. doi:10.1016/j.molimm.2013.06.002

[16]Bansal R. Method of inhibiting complement activation with factor Bb specific antibodies WO2009/029669A1. 2009.

[17]Safety and efficacy of IONIS-FB-Lrx in up to 120 patients 55 and older with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). NLM identifier: NCT03446144 Available from: https://clinicaltrials.gov/ct2/show/NCT03446144?term=IONIS-FB-Lrx&rank=2.

[18]Thurman JM, Kraus DM, Girardi G, et al. A novel inhibitor of the alternative complement pathway prevents antiphospholipid antibody-induced pregnancy loss in mice. Mol Immunol. 2005;42(1):87–97. doi:10.1016/j.molimm.2004.07.043

Promising new treatments for AMD

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Darko Savic
Darko Savic Jul 30, 2020

Using Senolytics to Treat AMD

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Jamila
Jamila Aug 03, 2020
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Shubhankar Kulkarni
Shubhankar Kulkarni4 months ago
Unity Biotechnology will launch its Phase 1 study of UBX1325 (a novel senolytic) for patients with diabetic macular edema. UBX1325 targets the BCL-xL pathway and destroys senescent cells, like Navitoclax. However, UBX1325 has overcome the serious side effects of Navitoclax. Something similar to UBX1325 can be helpful. (Reference: https://www.lifespan.io/news/a-new-senolytic-enters-human-trials/)

Retinal Pigment Epithelium Replacement Therapy

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Jamila
Jamila Aug 04, 2020

PHOTO-COAGULATION & ANTIOXIDANT SUPPLEMENTATION

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Mohammad Shazaib
Mohammad Shazaib Sep 13, 2020

Mitochondria Derived Peptides (MDPs) as potential treatment agents for AMD

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Subash Chapagain
Subash Chapagain Jan 11, 2021

[1]J. Blasiak, S. Glowacki, A. Kauppinen, and K. Kaarniranta, “Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration,” International Journal of Molecular Sciences, vol. 14, no. 2, pp. 2996–3010, 2013.

[2]F. Q. Liang and B. F. Godley, “Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration,” Experimental Eye Research, vol. 76, no. 4, pp. 397–403, 2003.

[3]Karunadharma, P.P.; Nordgaard, C.L.; Olsen, T.W.; Ferrington, D.A. Mitochondrial DNA. Damage as a potential mechanism for age-related macular degeneration. Invest Ophthalmol Vis. Sci. 2010, 51, 5470–5479.

[4]Fuku, N.; Pareja-Galeano, H.; Zempo, H.; Alis, R.; Arai, Y.; Lucia, A.; Hirose, N. The mitochondrial-derived peptide MOTS-c: A player in exceptional longevity? Aging Cell 2015, 14, 921–923.

[5]Hashimoto Y., Niikura T., Tajima H., Yasukawa T., Sudo H., Ito Y., Kita Y., Kawasumi M., Kouyama K., Doyu M., et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc. Natl. Acad. Sci. USA. 2001;98:6336–6341. doi:10.1073/pnas.101133498

[6]P. G. Sreekumar, K. Ishikawa, C. Spee et al., “The mitochondrial-derived peptide humanin protects RPE cells from oxidative stress, senescence, and mitochondrial dysfunction,” Investigative Ophthalmology & Visual Science, 2016, vol. 57, no. 3, pp. 1238–1253, 2016.

[7]Y. Hashimoto, T. Niikura, Y. Ito et al., “Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer’s disease-relevant insults,” Journal of Neuroscience, vol. 21, no. 23, pp. 9235–9245, 2001.

[8]Y. Hashimoto, H. Suzuki, S. Aiso, T. Niikura, I. Nishimoto, and M. Matsuoka, “Involvement of tyrosine kinases and STAT3 in Humanin-mediated neuroprotection,” Life Sciences, vol. 77, no. 24, pp. 3092–3104, 2005.

[9] S. J. Kim, N. Guerrero, G. Wassef et al., “The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling pathways and has age-dependent signaling differences in the hippocampus,” Oncotarget, vol. 7, no. 30, pp. 46899–46912, 2016.

[10]Yang L., Tan Z., Wang D., Xue L., Guan M.X., Huang T., Li R. Species identification through mitochondrial rRNA genetic analysis. Sci. Rep. 2014;4:4089. doi: 10.1038/srep04089.

[11]Nashine S., Cohen P., Nesburn A.B., Kuppermann B.D., Kenney M.C. Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration. Sci. Rep. 2018;8:15175. doi: 10.1038/s41598-018-33290-5.

P3HT nanoparticles

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Martina Pesce
Martina Pesce Nov 04, 2020
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Shubhankar Kulkarni
Shubhankar Kulkarni4 months ago
Martina Pesce That is really cool. Is that like a one-time therapy or does one need doses of the polymer for years? It is really helpful either way. It is also essential to check whether the natural chemicals in the eye (for example, proteases) damage the polymers.
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Martina Pesce
Martina Pesce4 months ago
Shubhankar Kulkarni
Apparently, after 8 months the nanoparticles were still in the same place and still working. I guess we will have to wait to know if the effect stays longer than this.

I'm quoting their work when they say that these nanoparticles have "high biocompatibility due
to the intrinsic affinity of their chemical structure with that of biomolecules".
Which is actually pretty great since they do not damage the eye and don't get damaged themself.

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