SpringerLink
Log in

Stages, pathogenesis, clinical management and advancements in therapies of age-related macular degeneration

  • Review
  • Published:
International Ophthalmology Aims and scope Submit manuscript

Abstract

Age-related macular degeneration (AMD) is a retinal degenerative disorder prevalent in the elderly population, which leads to the loss of central vision. The disease progression can be managed, if not prevented, either by blocking neovascularization (“wet” form of AMD) or by preserving retinal pigment epithelium and photoreceptor cells (“dry” form of AMD). Although current therapeutic modalities are moderately successful in delaying the progression and management of the disease, advances over the past years in regenerative medicine using iPSC, embryonic stem cells, advanced materials (including nanomaterials) and organ bio-printing show great prospects in restoring vision and efficient management of either forms of AMD. This review focuses on the molecular mechanism of the disease, model systems (both cellular and animal) used in studying AMD, the list of various regenerative therapies and the current treatments available. The article also highlights on the recent clinical trials using regenerative therapies and management of the disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Birch DG, Liang FQ (2007) Age-related macular degeneration: a target for nanotechnology derived medicines. Int J Nanomed 2(1):65–77

    Article  CAS  Google Scholar 

  2. Lin H, Xu H, Liang FQ, Liang H, Gupta P et al (2011) Mitochondrial DNA damage and repair in rpe associated with aging and age-related macular degeneration. Invest Ophthalmol Vis Sci 52(6):3521–3529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG (2009) Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol 54(1):96–117

    Article  PubMed  Google Scholar 

  4. Gu X, Neric NJ, Crabb JS, Crabb JW, Bhattacharya SK et al (2012) Age-related changes in the retinal pigment epithelium (RPE). PLoS ONE 7(6):e38673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dornonville de la Cour M (1993) Ion transport in the retinal pigment epithelium. A study with double barrelled ion-selective microelectrodes. Acta Ophthalmol Suppl 209:1–32

    Google Scholar 

  6. Hamann S (2002) Molecular mechanisms of water transport in the eye. Int Rev Cytol 215:395–431

    Article  CAS  PubMed  Google Scholar 

  7. Strauss O (2005) The retinal pigment epithelium in visual function. Physiol Rev 85(3):845–881

    Article  CAS  PubMed  Google Scholar 

  8. Negi A, Marmor MF (1984) Experimental serous retinal detachment and focal pigment epithelial damage. Arch Ophthalmol 102(3):445–449

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL et al (2008) Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 359(14):1456–1463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Collard CD, Vakeva A, Morrissey MA, Agah A, Rollins SA et al (2000) Complement activation after oxidative stress: role of the lectin complement pathway. Am J Pathol 156(5):1549–1556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gao ML, Wu KC, Deng WL, Lei XL, **ang L et al (2017) Toll-like receptor 3 activation initiates photoreceptor cell death in vivo and in vitro. Invest Ophthalmol Vis Sci 58(2):801–811

    Article  CAS  PubMed  Google Scholar 

  13. Murakami Y, Matsumoto H, Roh M, Giani A, Kataoka K et al (2014) Programmed necrosis, not apoptosis, is a key mediator of cell loss and damp-mediated inflammation in dsrna-induced retinal degeneration. Cell Death Differ 21(2):270–277

    Article  CAS  PubMed  Google Scholar 

  14. de Jong PT (2006) Age-related macular degeneration. N Engl J Med 355(14):1474–1485

    Article  PubMed  Google Scholar 

  15. Group* TEDPR (2004) Prevalence of open-angle glaucoma among adults in the united states. JAMA Ophthalmol 122(4):532–538

    Google Scholar 

  16. Pascolini D, Mariotti SP (2012) Global estimates of visual impairment: 2010. Br J Ophthalmol 96(5):614–618

    Article  PubMed  Google Scholar 

  17. Friedman DS, Wolfs RC, O’Colmain BJ, Klein BE, Taylor HR et al (2004) Prevalence of open-angle glaucoma among adults in the united states. Arch Ophthalmol 122(4):532–538

    Article  PubMed  Google Scholar 

  18. Wong WL, Su X, Li X, Cheung CM, Klein R et al (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2(2):e106-116

    Article  PubMed  Google Scholar 

  19. Klein R, Klein BE (2013) The prevalence of age-related eye diseases and visual impairment in aging: current estimates. Invest Ophthalmol Vis Sci 54(14):Orsf5–Orsf13

    Article  PubMed  PubMed Central  Google Scholar 

  20. Thapa R, Bajimaya S, Paudyal G, Khanal S, Tan S, Thapa SS, van Rens G (2017) Prevalence of and risk factors for age-related macular degeneration in Nepal: the Bhaktapur Retina Study. Clin Ophthalmol 11:963–972

    Article  PubMed  PubMed Central  Google Scholar 

  21. Guyer DR, Fine SL, Maguire MG, Hawkins BS, Owens SL et al (1986) Subfoveal choroidal neovascular membranes in age-related macular degeneration. Visual prognosis in eyes with relatively good initial visual acuity. Arch Ophthalmol 104(5):702–705

    Article  CAS  PubMed  Google Scholar 

  22. Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G et al (2008) The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology 115(1):116–126

    Article  PubMed  Google Scholar 

  23. Erke MG, Bertelsen G, Peto T, Sjølie AK, Lindekleiv H, Njølstad I (2014) Cardiovascular risk factors associated with age-related macular degeneration: the tromsø study. Acta Ophthalmol 92(7):662–669

    Article  PubMed  Google Scholar 

  24. Rudnicka AR, Jarrar Z, Wormald R, Cook DG, Fletcher A, Owen CG (2012) Age and gender variations in age-related macular degeneration prevalence in populations of European ancestry: a meta-analysis. Ophthalmology 119(3):571–580

    Article  PubMed  Google Scholar 

  25. Klein R, Meuer SM, Knudtson MD, Iyengar SK, Klein BE (2008) The epidemiology of retinal reticular drusen. Am J Ophthalmol 145(2):317–326

    Article  PubMed  Google Scholar 

  26. Klein ML, Ferris FL, 3rd, Francis PJ, Lindblad AS, Chew EY et al (2010) Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 117(8):1554–1559, 1559.e1551

  27. Schlanitz FG, Baumann B, Kundi M, Sacu S, Baratsits M et al (2017) Drusen volume development over time and its relevance to the course of age-related macular degeneration. Br J Ophthalmol 101(2):198–203

    Article  PubMed  Google Scholar 

  28. Al Gwairi O, Thach L, Zheng W, Osman N, Little PJ (2016) Cellular and molecular pathology of age-related macular degeneration: potential role for proteoglycans. J Ophthalmol 2016:2913612

    Article  PubMed  PubMed Central  Google Scholar 

  29. van Lookeren CM, LeCouter J, Yaspan BL, Ye W (2014) Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol 232(2):151–164

    Article  Google Scholar 

  30. Boulton M, Dayhaw-Barker P (2001) The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye (Lond) 15(Pt 3):384–389

    Article  CAS  PubMed  Google Scholar 

  31. Köse C, Sevik U, Gençalioğlu O (2008) Automatic segmentation of age-related macular degeneration in retinal fundus images. Comput Biol Med 38(5):611–619

    Article  PubMed  Google Scholar 

  32. van Grinsven MJ, Lechanteur YT, van de Ven JP, van Ginneken B, Hoyng CB et al (2013) Automatic drusen quantification and risk assessment of age-related macular degeneration on color fundus images. Invest Ophthalmol Vis Sci 54(4):3019–3027

    Article  PubMed  Google Scholar 

  33. Bartlett H, Eperjesi F (2007) Use of fundus imaging in quantification of age-related macular change. Surv Ophthalmol 52(6):655–671

    Article  PubMed  Google Scholar 

  34. Mettu PS, Wielgus AR, Ong SS, Cousins SW (2012) Retinal pigment epithelium response to oxidant injury in the pathogenesis of early age-related macular degeneration. Mol Asp Med 33(4):376–398

    Article  CAS  Google Scholar 

  35. Seddon JM, McLeod DS, Bhutto IA, Villalonga MB, Silver RE et al (2016) Histopathological insights into choroidal vascular loss in clinically documented cases of age-related macular degeneration. JAMA Ophthalmol 134(11):1272–1280

    Article  PubMed  PubMed Central  Google Scholar 

  36. Borrelli E, Sarraf D, Freund KB, Sadda SR (2018) Oct angiography and evaluation of the choroid and choroidal vascular disorders. Prog Retinal Eye Res 67:30–55

    Article  Google Scholar 

  37. Cherepanoff S, McMenamin P, Gillies MC, Kettle E, Sarks SH (2010) Bruch’s membrane and choroidal macrophages in early and advanced age-related macular degeneration. Br J Ophthalmol 94(7):918–925

    Article  CAS  PubMed  Google Scholar 

  38. Ashraf M, Souka AAR (2017) Aflibercept in age-related macular degeneration: evaluating its role as a primary therapeutic option. Eye (Lond) 31(11):1523–1536

    Article  CAS  PubMed  Google Scholar 

  39. Friberg TR, Bilonick RA, Brennen P (2012) Is drusen area really so important? An assessment of risk of conversion to neovascular amd based on computerized measurements of drusen. Invest Ophthalmol Vis Sci 53(4):1742–1751

    Article  PubMed  PubMed Central  Google Scholar 

  40. Vitale S, Agrón E, Clemons TE, Keenan TDL, Domalpally A et al (2020) Association of 2-year progression along the AREDS AMD scale and development of late age-related macular degeneration or loss of visual acuity: AREDS report 41. JAMA Ophthalmol 138(6):610–617

    Article  PubMed  Google Scholar 

  41. Ambati J, Atkinson JP, Gelfand BD (2013) Immunology of age-related macular degeneration. Nat Rev Immunol 13(6):438–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. De Jong PTVM (2018) Elusive drusen and changing terminology of amd. Eye 32(5):904–914

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH et al (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-bruch’s membrane interface in aging and age-related macular degeneration. Prog Retinal Eye Res 20(6):705–732

    Article  CAS  Google Scholar 

  45. Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 14(7):835–846

    Article  CAS  PubMed  Google Scholar 

  46. Gu X, Meer SG, Miyagi M, Rayborn ME, Hollyfield JG et al (2003) Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for age-related macular degeneration. J Biol Chem 278(43):42027–42035

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT et al (2010) The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retinal Eye Res 29(2):95–112

    Article  CAS  Google Scholar 

  49. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ et al (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102(20):7227–7232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Johnson LV, Leitner WP, Staples MK, Anderson DH (2001) Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res 73(6):887–896

    Article  CAS  PubMed  Google Scholar 

  51. Ishibashi T, Murata T, Hangai M, Nagai R, Horiuchi S et al (1998) Advanced glycation end products in age-related macular degeneration. Arch Ophthalmol 116(12):1629–1632

    Article  CAS  PubMed  Google Scholar 

  52. Crabb JW, Miyagi M, Gu X, Shadrach K, West KA et al (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 99(23):14682–14687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Javitt NB, Javitt JC (2009) The retinal oxysterol pathway: a unifying hypothesis for the cause of age-related macular degeneration. Curr Opin Ophthalmol 20(3):151–157

    Article  PubMed  Google Scholar 

  54. Mullins RF, Johnson LV, Anderson DH, Hageman GS (1997) Characterization of drusen-associated glycoconjugates. Ophthalmology 104(2):288–294

    Article  CAS  PubMed  Google Scholar 

  55. Kaarniranta K, Salminen A (2009) Age-related macular degeneration: activation of innate immunity system via pattern recognition receptors. J Mol Med (Berl) 87(2):117–123

    Article  CAS  PubMed  Google Scholar 

  56. Yu DY, Cringle SJ (2001) Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retinal Eye Res 20(2):175–208

    Article  CAS  Google Scholar 

  57. Tokarz P, Kaarniranta K, Blasiak J (2013) Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD). Biogerontology 14(5):461–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Arstila AU, Smith MA, Trump BF (1972) Microsomal lipid peroxidation: morphological characterization. Science 175(4021):530–533

    Article  CAS  PubMed  Google Scholar 

  59. De La Paz MA, Anderson RE (1992) Lipid peroxidation in rod outer segments. Role of hydroxyl radical and lipid hydroperoxides. Invest Ophthalmol Vis Sci 33(7):2091–2096

    PubMed  Google Scholar 

  60. Shaw PX, Zhang L, Zhang M, Du H, Zhao L et al (2012) Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Proc Natl Acad Sci 109(34):13757–13762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shaw PX, Hörkkö S, Chang M-K, Curtiss LK, Palinski W et al (2000) Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Investig 105(12):1731–1740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sparrow JR, Boulton M (2005) RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res 80(5):595–606

    Article  CAS  PubMed  Google Scholar 

  63. Wu Y, Yanase E, Feng X, Siegel MM, Sparrow JR (2010) Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration. Proc Natl Acad Sci USA 107(16):7275–7280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sparrow JR, Nakanishi K, Parish CA (2000) The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci 41(7):1981–1989

    CAS  PubMed  Google Scholar 

  65. Sparrow JR, Vollmer-Snarr HR, Zhou J, Jang YP, Jockusch S et al (2003) A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation. J Biol Chem 278(20):18207–18213

    Article  CAS  PubMed  Google Scholar 

  66. Pétrilli V, Dostert C, Muruve DA, Tschopp J (2007) The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol 19(6):615–622

    Article  PubMed  Google Scholar 

  67. Masters SL, De Nardo D (2014) Innate immunity. Curr Opin Immunol 26:v–vi

    Article  CAS  PubMed  Google Scholar 

  68. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11(5):373–384

    Article  CAS  PubMed  Google Scholar 

  69. Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30:16–34

    Article  CAS  PubMed  Google Scholar 

  70. Bianchi ME (2007) Damps, pamps and alarmins: all we need to know about danger. J Leukoc Biol 81(1):1–5

    Article  CAS  PubMed  Google Scholar 

  71. Miyake K (2007) Innate immune sensing of pathogens and danger signals by cell surface toll-like receptors. Semin Immunol 19(1):3–10

    Article  CAS  PubMed  Google Scholar 

  72. Yamada Y, Ishibashi K, Ishibashi K, Bhutto IA, Tian J et al (2006) The expression of advanced glycation endproduct receptors in RPE cells associated with basal deposits in human maculas. Exp Eye Res 82(5):840–848

    Article  CAS  PubMed  Google Scholar 

  73. Howes KA, Liu Y, Dunaief JL, Milam A, Frederick JM et al (2004) Receptor for advanced glycation end products and age-related macular degeneration. Invest Ophthalmol Vis Sci 45(10):3713–3720

    Article  PubMed  Google Scholar 

  74. Holtkamp GM, Kijlstra A, Peek R, de Vos AF (2001) Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes. Prog Retinal Eye Res 20(1):29–48

    Article  CAS  Google Scholar 

  75. Yang D, Elner SG, Bian ZM, Till GO, Petty HR et al (2007) Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res 85(4):462–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Boulton M, McKechnie NM, Breda J et al (1989) The formation of autofluorescent granules in cultured human RPE. Invest Ophthalmol Vis Sci 30:82–89

    CAS  PubMed  Google Scholar 

  77. Yin D (1996) Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Radic Biol Med 21(6):871–888

    Article  CAS  PubMed  Google Scholar 

  78. Vohra RS, Murphy JE, Walker JH, Ponnambalam S, Homer-Vanniasinkam S (2006) Atherosclerosis and the lectin-like oxidized low-density lipoprotein scavenger receptor. Trends Cardiovasc Med 16(2):60–64

    Article  CAS  PubMed  Google Scholar 

  79. Duncan KG, Bailey KR, Kane JP, Schwartz DM (2002) Human retinal pigment epithelial cells express scavenger receptors BI and BII. Biochem Biophys Res Commun 292(4):1017–1022

    Article  CAS  PubMed  Google Scholar 

  80. Xu H, Chen M, Manivannan A, Lois N, Forrester JV (2008) Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7(1):58–68

    Article  CAS  PubMed  Google Scholar 

  81. Li YM, Dickson DW (1997) Enhanced binding of advanced glycation endproducts (AGE) by the ApoE4 isoform links the mechanism of plaque deposition in Alzheimer’s disease. Neurosci Lett 226(3):155–158

    Article  CAS  PubMed  Google Scholar 

  82. Tabaton M, Perry G, Smith M, Vitek M, Angelini G et al (1997) Is amyloid beta-protein glycated in Alzheimer’s disease? NeuroReport 8(4):907–909

    Article  CAS  PubMed  Google Scholar 

  83. Hammes HP, Weiss A, Hess S, Araki N, Horiuchi S et al (1996) Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina. Lab Invest 75(3):325–338

    CAS  PubMed  Google Scholar 

  84. Lin T, Walker GB, Kurji K, Fang E, Law G et al (2013) Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye. Cytokine 62(3):369–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ohgami N, Nagai R, Ikemoto M, Arai H, Kuniyasu A et al (2001) Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products. J Biol Chem 276(5):3195–3202

    Article  CAS  PubMed  Google Scholar 

  86. Sparrow JR, Cai B, Fishkin N, Jang YP, Krane S et al (2003) A2E, a fluorophore of RPE lipofuscin: can it cause rpe degeneration? Adv Exp Med Biol 533:205–211

    Article  CAS  PubMed  Google Scholar 

  87. Terman A, Brunk UT (2004) Lipofuscin. Int J Biochem Cell Biol 36(8):1400–1404

    Article  CAS  PubMed  Google Scholar 

  88. Nordgaard CL, Karunadharma PP, Feng X, Olsen TW, Ferrington DA (2008) Mitochondrial proteomics of the retinal pigment epithelium at progressive stages of age-related macular degeneration. Invest Ophthalmol Vis Sci 49(7):2848–2855

    Article  PubMed  Google Scholar 

  89. Algvere PV, Seregard S (2002) Age-related maculopathy: pathogenetic features and new treatment modalities. Acta Ophthalmol Scand 80(2):136–143

    Article  PubMed  Google Scholar 

  90. Algvere PV, Marshall J, Seregard S (2006) Age-related maculopathy and the impact of blue light hazard. Acta Ophthalmol Scand 84(1):4–15

    Article  CAS  PubMed  Google Scholar 

  91. Ferrington DA, Sinha D, Kaarniranta K (2016) Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration. Prog Retinal Eye Res 51:69–89

    Article  CAS  Google Scholar 

  92. Ryhänen T, Hyttinen JM, Kopitz J, Rilla K, Kuusisto E et al (2009) Crosstalk between Hsp70 molecular chaperone, lysosomes and proteasomes in autophagy-mediated proteolysis in human retinal pigment epithelial cells. J Cell Mol Med 13(9b):3616–3631

    Article  PubMed  Google Scholar 

  93. Kaarniranta K, Salminen A, Eskelinen EL, Kopitz J (2009) Heat shock proteins as gatekeepers of proteolytic pathways-implications for age-related macular degeneration (AMD). Ageing Res Rev 8(2):128–139

    Article  CAS  PubMed  Google Scholar 

  94. Blasiak J, Glowacki S, Kauppinen A, Kaarniranta K (2013) Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration. Int J Mol Sci 14(2):2996–3010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Schütt F, Bergmann M, Holz FG, Kopitz J (2002) Isolation of intact lysosomes from human RPE cells and effects of A2-E on the integrity of the lysosomal and other cellular membranes. Graefes Arch Clin Exp Ophthalmol 240(12):983–988

    Article  PubMed  Google Scholar 

  96. Bergmann M, Schütt F, Holz FG, Kopitz J (2004) Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration. FASEB J 18(3):562–564

    Article  CAS  PubMed  Google Scholar 

  97. Vives-Bauza C, Anand M, Shiraz AK, Magrane J, Gao J et al (2008) The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells. J Biol Chem 283(36):24770–24780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Valapala M, Wilson C, Hose S, Bhutto IA, Grebe R et al (2014) Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/βA3/A1-crystallin via V-ATPase-MTORC1 signaling. Autophagy 10(3):480–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hyttinen JM, Amadio M, Viiri J, Pascale A, Salminen A et al (2014) Clearance of misfolded and aggregated proteins by aggrephagy and implications for aggregation diseases. Ageing Res Rev 18:16–28

    Article  CAS  PubMed  Google Scholar 

  100. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Arjamaa O, Nikinmaa M, Salminen A, Kaarniranta K (2009) Regulatory role of HIF-1α in the pathogenesis of age-related macular degeneration (AMD). Ageing Res Rev 8(4):349–358

    Article  CAS  PubMed  Google Scholar 

  102. Hyttinen JM, Niittykoski M, Salminen A, Kaarniranta K (2013) Maturation of autophagosomes and endosomes: a key role for Rab7. Biochim Biophys Acta 1833(3):503–510

    Article  CAS  PubMed  Google Scholar 

  103. Zucchi PC, Zick M (2011) Membrane fusion catalyzed by a Rab, SNAREs, and SNARE chaperones is accompanied by enhanced permeability to small molecules and by lysis. Mol Biol Cell 22(23):4635–4646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Behrends C, Sowa ME, Gygi SP, Harper JW (2010) Network organization of the human autophagy system. Nature 466(7302):68–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cullen V, Lindfors M, Ng J, Paetau A, Swinton E et al (2009) Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity in vivo. Mol Brain 2:5

    Article  PubMed  PubMed Central  Google Scholar 

  106. O’Neil J, Hoppe G, Sayre LM, Hoff HF (1997) Inactivation of cathepsin B by oxidized LDL involves complex formation induced by binding of putative reactive sites exposed at low PH to thiols on the enzyme. Free Radic Biol Med 23(2):215–225

    Article  CAS  PubMed  Google Scholar 

  107. Kaarniranta K, Sinha D, Blasiak J, Kauppinen A, Veréb Z et al (2013) Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration. Autophagy 9(7):973–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Krohne TU, Kaemmerer E, Holz FG, Kopitz J (2010) Lipid peroxidation products reduce lysosomal protease activities in human retinal pigment epithelial cells via two different mechanisms of action. Exp Eye Res 90(2):261–266

    Article  CAS  PubMed  Google Scholar 

  109. Perusek L, Sahu B, Parmar T, Maeno H, Arai E, Le YZ, Subauste CS, Chen Y, Palczewski K, Maeda A (2015) Di-retinoid-pyridinium-ethanolamine (A2E) accumulation and the maintenance of the visual cycle are independent of Atg7-mediated autophagy in the retinal pigmented epithelium. Mol Bases Dis Cell Biol 290(48):29035–29044

    CAS  Google Scholar 

  110. Finnemann SC, Leung LW, Rodriguez-Boulan E (2002) The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proc Natl Acad Sci USA 99(6):3842–3847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lamb LE, Simon JD (2004) A2e: a component of ocular lipofuscin. Photochem Photobiol 79(2):127–136

    Article  CAS  PubMed  Google Scholar 

  112. Golestaneh N, Chu Y, **ao YY, Stoleru GL, Theos AC (2017) Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration. Cell Death Dis 8(1):e2537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Mizushima N, Yoshimori T (2007) How to interpret LC3 immunoblotting. Autophagy 3(6):542–545

    Article  CAS  PubMed  Google Scholar 

  114. Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM (2016) LC3/gabarap family proteins: autophagy-(un)related functions. FASEB J 30(12):3961–3978

    Article  CAS  PubMed  Google Scholar 

  115. Nandrot EF (2014) Animal models, in “the quest to decipher RPE phagocytosis.” Adv Exp Med Biol 801:77–83

    Article  PubMed  Google Scholar 

  116. Fine SL (2005) Age-related macular degeneration 1969–2004: a 35-year personal perspective. Am J Ophthalmol 139(3):405–420

    Article  PubMed  Google Scholar 

  117. Kopitz J, Holz FG, Kaemmerer E, Schutt F (2004) Lipids and lipid peroxidation products in the pathogenesis of age-related macular degeneration. Biochimie 86(11):825–831

    Article  CAS  PubMed  Google Scholar 

  118. Kinnunen K, Petrovski G, Moe MC, Berta A, Kaarniranta K (2012) Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration. Acta Ophthalmol 90(4):299–309

    Article  CAS  PubMed  Google Scholar 

  119. Wolf G (2003) Lipofuscin and macular degeneration. Nutr Rev 61(10):342–346

    Article  PubMed  Google Scholar 

  120. Tate DJ Jr, Miceli MV, Newsome DA (1995) Phagocytosis and H2O2 induce catalase and metallothionein gene expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 36(7):1271–1279

    PubMed  Google Scholar 

  121. Shang F, Taylor A (2004) Function of the ubiquitin proteolytic pathway in the eye. Exp Eye Res 78(1):1–14

    Article  CAS  PubMed  Google Scholar 

  122. Lutty G, Grunwald J, Majji AB, Uyama M, Yoneya S (1999) Changes in choriocapillaris and retinal pigment epithelium in age-related macular degeneration. Mol Vis 5:35

    CAS  PubMed  Google Scholar 

  123. Bhutto IA, McLeod DS, Hasegawa T, Kim SY, Merges C et al (2006) Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration. Exp Eye Res 82(1):99–110

    Article  CAS  PubMed  Google Scholar 

  124. Holekamp NM, Bouck N, Volpert O (2002) Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol 134(2):220–227

    Article  CAS  PubMed  Google Scholar 

  125. Ardeljan CP, Ardeljan D, Abu-Asab M, Chan CC (2014) Inflammation and cell death in age-related macular degeneration: an immunopathological and ultrastructural model. J Clin Med 3(4):1542–1560

    Article  PubMed  PubMed Central  Google Scholar 

  126. Hanus J, Kolkin A, Chimienti J, Botsay S, Wang S (2015) 4-acetoxyphenol prevents rpe oxidative stress-induced necrosis by functioning as an NRF2 stabilizer. Invest Ophthalmol Vis Sci 56(9):5048–5059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS et al (2013) NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 54(1):110–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gelfand BD, Wright CB, Kim Y, Yasuma T, Yasuma R et al (2015) Iron toxicity in the retina requires Alu RNA and the NLRP3 inflammasome. Cell Rep 11(11):1686–1693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hanus J, Zhang H, Wang Z, Liu Q, Zhou Q et al (2013) Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells. Cell Death Dis 4(12):e965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Brandstetter C, Patt J, Holz FG, Krohne TU (2016) Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B 161:177–183

    Article  CAS  PubMed  Google Scholar 

  131. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119(3):493–501

    Article  CAS  PubMed  Google Scholar 

  132. Xu GZ, Li WW, Tso MO (1996) Apoptosis in human retinal degenerations. Trans Am Ophthalmol Soc 94:411–430; discussion 430–411

  133. Dunaief JL, Dentchev T, Ying GS, Milam AH (2002) The role of apoptosis in age-related macular degeneration. Arch Ophthalmol 120(11):1435–1442

    Article  PubMed  Google Scholar 

  134. Zacks DN, Hanninen V, Pantcheva M, Ezra E, Grosskreutz C et al (2003) Caspase activation in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 44(3):1262–1267

    Article  PubMed  Google Scholar 

  135. Zacks DN, Zheng QD, Han Y, Bakhru R, Miller JW (2004) Fas-mediated apoptosis and its relation to intrinsic pathway activation in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci 45(12):4563–4569

    Article  PubMed  Google Scholar 

  136. Nakazawa T, Kayama M, Ryu M, Kunikata H, Watanabe R et al (2011) Tumor necrosis factor-alpha mediates photoreceptor death in a rodent model of retinal detachment. Invest Ophthalmol Vis Sci 52(3):1384–1391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nakazawa T, Matsubara A, Noda K, Hisatomi T, She H et al (2006) Characterization of cytokine responses to retinal detachment in rats. Mol Vis 12:867–878

    CAS  PubMed  Google Scholar 

  138. Hisatomi T, Sakamoto T, Murata T, Yamanaka I, Oshima Y et al (2001) Relocalization of apoptosis-inducing factor in photoreceptor apoptosis induced by retinal detachment in vivo. Am J Pathol 158(4):1271–1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Trichonas G, Murakami Y, Thanos A, Morizane Y, Kayama M et al (2010) Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis. Proc Natl Acad Sci USA 107(50):21695–21700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hisatomi T, Nakazawa T, Noda K, Almulki L, Miyahara S et al (2008) HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice. J Clin Invest 118(6):2025–2038

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhu Y, Zhao KK, Tong Y, Zhou YL, Wang YX et al (2016) Exogenous nad(+) decreases oxidative stress and protects H2O2-treated RPE cells against necrotic death through the up-regulation of autophagy. Sci Rep 6:26322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714

    Article  CAS  PubMed  Google Scholar 

  143. Arimura N, Ki-i Y, Hashiguchi T, Kawahara K, Biswas KK et al (2009) Intraocular expression and release of high-mobility group box 1 protein in retinal detachment. Lab Invest 89(3):278–289

    Article  CAS  PubMed  Google Scholar 

  144. Rebello G, Ramesar R, Vorster A, Roberts L, Ehrenreich L et al (2004) Apoptosis-inducing signal sequence mutation in carbonic anhydrase IV identified in patients with the RP17 form of retinitis pigmentosa. Proc Natl Acad Sci USA 101(17):6617–6622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Gorbatyuk MS, Knox T, LaVail MM, Gorbatyuk OS, Noorwez SM et al (2010) Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc Natl Acad Sci USA 107(13):5961–5966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tam BM, Moritz OL (2006) Characterization of rhodopsin P23H-induced retinal degeneration in a Xenopus laevis model of retinitis pigmentosa. Invest Ophthalmol Vis Sci 47(8):3234–3241

    Article  PubMed  Google Scholar 

  147. Shinohara T, Mulhern ML, Madson CJ (2008) Silencing gene therapy for mutant membrane, secretory, and lipid proteins in retinitis pigmentosa (RP). Med Hypotheses 70(2):378–380

    Article  CAS  PubMed  Google Scholar 

  148. Sanges D, Marigo V (2006) Cross-talk between two apoptotic pathways activated by endoplasmic reticulum stress: differential contribution of caspase-12 and AIF. Apoptosis 11(9):1629–1641

    Article  CAS  PubMed  Google Scholar 

  149. Yang LP, Wu LM, Guo XJ, Tso MO (2007) Activation of endoplasmic reticulum stress in degenerating photoreceptors of the rd1 mouse. Invest Ophthalmol Vis Sci 48(11):5191–5198

    Article  PubMed  Google Scholar 

  150. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K (2013) Seven-year outcomes in ranibizumab-treated patients in anchor, marina, and horizon: a multicenter cohort study (seven-up). Ophthalmology 120(11):2292–2299

    Article  PubMed  Google Scholar 

  151. Peyman GA, Blinder KJ, Paris CL, Alturki W, Nelson NC Jr et al (1991) A technique for retinal pigment epithelium transplantation for age-related macular degeneration secondary to extensive subfoveal scarring. Ophthalmic Surg 22(2):102–108

    CAS  PubMed  Google Scholar 

  152. Algvere PV, Gouras P, Dafgard Kopp E (1999) Long-term outcome of RPE allografts in non-immunosuppressed patients with amd. Eur J Ophthalmol 9(3):217–230

    Article  CAS  PubMed  Google Scholar 

  153. Renno RZ, Miller JW (2001) Photosensitizer delivery for photodynamic therapy of choroidal neovascularization. Adv Drug Deliv Rev 52(1):63–78

    Article  CAS  PubMed  Google Scholar 

  154. Han DP, McAllister JT, Weinberg DV, Kim JE, Wirostko WJ (2010) Combined intravitreal anti-VEGF and verteporfin photodynamic therapy for juxtafoveal and extrafoveal choroidal neovascularization as an alternative to laser photocoagulation. Eye (Lond) 24(4):713–716

    Article  CAS  PubMed  Google Scholar 

  155. Chew EY, Clemons TE, Agrón E, Sperduto RD, SanGiovanni JP et al (2014) Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36. JAMA Ophthalmol 132(3):272–277

    Article  PubMed  Google Scholar 

  156. Chew EY, Clemons TE, Keenan TDL, Agron E, Malley CE et al (2021) The results of the 10 year follow-on study of the age-related eye disease study 2 (AREDS2). Invest Ophthalmol Vis Sci 62(8):1215–1215

    Google Scholar 

  157. Group* TA-REDSR (2013) Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 309(19):2005–2015

    Article  Google Scholar 

  158. Chew EY, Clemons TE, Agrón E, Domalpally A, Keenan TDL et al (2022) Long-term outcomes of adding lutein/zeaxanthin and ω-3 fatty acids to the AREDS supplements on age-related macular degeneration progression: AREDS2 report. JAMA Ophthalmol 140:692–698

    Article  PubMed  PubMed Central  Google Scholar 

  159. da Cruz L, Dorn JD, Humayun MS, Dagnelie G, Handa J et al (2016) Five-year safety and performance results from the Argus II retinal prosthesis system clinical trial. Ophthalmology 123(10):2248–2254

    Article  PubMed  Google Scholar 

  160. Lewis PM, Ayton LN, Guymer RH, Lowery AJ, Blamey PJ et al (2016) Advances in implantable bionic devices for blindness: a review. ANZ J Surg 86(9):654–659

    Article  PubMed  PubMed Central  Google Scholar 

  161. Jung JH, Aloni D, Yitzhaky Y, Peli E (2015) Active confocal imaging for visual prostheses. Vis Res 111(Pt B):182–196

    Article  PubMed  Google Scholar 

  162. Luo G, Peli E (2011) Development and evaluation of vision rehabilitation devices. In: Conference proceedings: annual international conference of the IEEE engineering in medicine and biology society, pp 5228–5231

  163. Gonzalez-Cordero A, Kruczek K, Naeem A, Fernando M, Kloc M et al (2017) Recapitulation of human retinal development from human pluripotent stem cells generates transplantable populations of cone photoreceptors. Stem Cell Rep 9(3):820–837

    Article  Google Scholar 

  164. Kruczek K, Gonzalez-Cordero A, Goh D, Naeem A, Jonikas M et al (2017) Differentiation and transplantation of embryonic stem cell-derived cone photoreceptors into a mouse model of end-stage retinal degeneration. Stem Cell Rep 8(6):1659–1674

    Article  CAS  Google Scholar 

  165. Decembrini S, Koch U, Radtke F, Moulin A, Arsenijevic Y (2014) Derivation of traceable and transplantable photoreceptors from mouse embryonic stem cells. Stem Cell Rep 2(6):853–865

    Article  CAS  Google Scholar 

  166. Wahlin KJ, Maruotti JA, Sripathi SR, Ball J, Angueyra JM et al (2017) Photoreceptor outer segment-like structures in long-term 3D retinas from human pluripotent stem cells. Sci Rep 7(1):766

    Article  PubMed  PubMed Central  Google Scholar 

  167. Zhong X, Gutierrez C, Xue T, Hampton C, Vergara MN et al (2014) Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 5:4047

    Article  CAS  PubMed  Google Scholar 

  168. Chang TS, Bressler NM, Fine JT, Dolan CM, Ward J et al (2007) Improved vision-related function after ranibizumab treatment of neovascular age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 125(11):1460–1469

    Article  CAS  PubMed  Google Scholar 

  169. Fernandez-Robredo P, Sancho A, Johnen S, Recalde S, Gama N et al (2014) Current treatment limitations in age-related macular degeneration and future approaches based on cell therapy and tissue engineering. J Ophthalmol 2014:510285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Arai S, Thomas BB, Seiler MJ, Aramant RB, Qiu G et al (2004) Restoration of visual responses following transplantation of intact retinal sheets in rd mice. Exp Eye Res 79(3):331–341

    Article  CAS  PubMed  Google Scholar 

  171. Ghosh F, Wong F, Johansson K, Bruun A, Petters RM (2004) Transplantation of full-thickness retina in the rhodopsin transgenic pig. Retina 24(1):98–109

    Article  PubMed  Google Scholar 

  172. Aramant RB, Seiler MJ (2002) Transplanted sheets of human retina and retinal pigment epithelium develop normally in nude rats. Exp Eye Res 75(2):115–125

    Article  CAS  PubMed  Google Scholar 

  173. Eberle D, Santos-Ferreira T, Grahl S, Ader M (2014) Subretinal transplantation of macs purified photoreceptor precursor cells into the adult mouse retina. J Vis Exp 84:e50932

    Google Scholar 

  174. MacLaren RE, Pearson RA, MacNeil A, Douglas RH, Salt TE et al (2006) Retinal repair by transplantation of photoreceptor precursors. Nature 444(7116):203–207

    Article  CAS  PubMed  Google Scholar 

  175. Liu Y, Chen SJ, Li SY, Qu LH, Meng XH et al (2017) Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients. Stem Cell Res Ther 8(1):209

    Article  PubMed  PubMed Central  Google Scholar 

  176. Klassen H, Kiilgaard JF, Warfvinge K, Samuel MS, Prather RS et al (2012) Photoreceptor differentiation following transplantation of allogeneic retinal progenitor cells to the dystrophic rhodopsin Pro347Leu transgenic pig. Stem Cells Int 2012:939801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Jones MK, Lu B, Saghizadeh M, Wang S (2016) Gene expression changes in the retina following subretinal injection of human neural progenitor cells into a rodent model for retinal degeneration. Mol Vis 22:472–490

    CAS  PubMed  PubMed Central  Google Scholar 

  178. McGill TJ, Cottam B, Lu B, Wang S, Girman S et al (2012) Transplantation of human central nervous system stem cells-neuroprotection in retinal degeneration. Eur J Neurosci 35(3):468–477

    Article  PubMed  Google Scholar 

  179. Tham YC, Li X, Wong TY, Quigley HA, Aung T et al (2014) Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121(11):2081–2090

    Article  PubMed  Google Scholar 

  180. Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C et al (2017) Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 376(11):1038–1046

    Article  CAS  PubMed  Google Scholar 

  181. Kamao H, Mandai M, Ohashi W, Hirami Y, Kurimoto Y et al (2017) Evaluation of the surgical device and procedure for extracellular matrix-scaffold-supported human iPSC-derived retinal pigment epithelium cell sheet transplantation. Invest Ophthalmol Vis Sci 58(1):211–220

    Article  PubMed  Google Scholar 

  182. Assawachananont J, Mandai M, Okamoto S, Yamada C, Eiraku M et al (2014) Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice. Stem Cell Rep 2(5):662–674

    Article  Google Scholar 

  183. Thomas BB, Zhu D, Zhang L, Thomas PB, Hu Y et al (2016) Survival and functionality of hESC-derived retinal pigment epithelium cells cultured as a monolayer on polymer substrates transplanted in RCS rats. Invest Ophthalmol Vis Sci 57(6):2877–2887

    Article  CAS  PubMed  Google Scholar 

  184. Wang J, Westenskow PD, Fang M, Friedlander M, Siuzdak G (2016) Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation. Philos Trans R Soc Math Phys Eng Sci 374:20150376

    Google Scholar 

  185. Carr AJ, Vugler AA, Hikita ST, Lawrence JM, Gias C et al (2009) Protective effects of human iPS-derived retinal pigment epithelium cell transplantation in the retinal dystrophic rat. PLoS ONE 4(12):e8152

    Article  PubMed  PubMed Central  Google Scholar 

  186. Becker S, Eastlake K, Jayaram H, Jones MF, Brown RA et al (2016) Allogeneic transplantation of muller-derived retinal ganglion cells improves retinal function in a feline model of ganglion cell depletion. Stem Cells Transl Med 5(2):192–205

    Article  PubMed  Google Scholar 

  187. Singhal S, Bhatia B, Jayaram H, Becker S, Jones MF et al (2012) Human muller glia with stem cell characteristics differentiate into retinal ganglion cell (RGC) precursors in vitro and partially restore RGC function in vivo following transplantation. Stem Cells Transl Med 1(3):188–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Wang SZ, Ma W, Yan RT, Mao W (2010) Generating retinal neurons by reprogramming retinal pigment epithelial cells. Expert Opin Biol Ther 10(8):1227–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Aftab U, Jiang C, Tucker B, Kim JY, Klassen H et al (2009) Growth kinetics and transplantation of human retinal progenitor cells. Exp Eye Res 89(3):301–310

    Article  CAS  PubMed  Google Scholar 

  190. Ashtari M, Zhang H, Cook PA, Cyckowski LL, Shindler KS et al (2015) Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis. Sci Transl Med 7(296):296ra110

    Article  PubMed  PubMed Central  Google Scholar 

  191. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F et al (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358(21):2240–2248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Bertolotti E, Neri A, Camparini M, Macaluso C, Marigo V (2014) Stem cells as source for retinal pigment epithelium transplantation. Prog Retinal Eye Res 42:130–144

    Article  CAS  Google Scholar 

  193. Schwartz SD, Hubschman JP, Heilwell G, Franco-Cardenas V, Pan CK et al (2012) Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 379(9817):713–720

    Article  CAS  PubMed  Google Scholar 

  194. Song WK, Park KM, Kim HJ, Lee JH, Choi J et al (2015) Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients. Stem Cell Rep 4(5):860–872

    Article  CAS  Google Scholar 

  195. Han L, Ma Z, Wang C, Dou H, Hu Y et al (2013) Autologous transplantation of simple retinal pigment epithelium sheet for massive submacular hemorrhage associated with pigment epithelium detachment. Invest Ophthalmol Vis Sci 54(7):4956–4963

    Article  PubMed  Google Scholar 

  196. Kelley MW, Turner JK, Reh TA (1995) Regulation of proliferation and photoreceptor differentiation in fetal human retinal cell cultures. Invest Ophthalmol Vis Sci 36(7):1280–1289

    CAS  PubMed  Google Scholar 

  197. Sinha D, Phillips J, Joseph Phillips M, Gamm DM (2016) Mimicking retinal development and disease with human pluripotent stem cells. Invest Ophthalmol Vis Sci 57(5):ORSFf1–ORSFf9

    Article  CAS  PubMed  Google Scholar 

  198. Ohlemacher SK, Iglesias CL, Sridhar A, Gamm DM, Meyer JS (2015) Generation of highly enriched populations of optic vesicle-like retinal cells from human pluripotent stem cells. Curr Protoc Stem Cell Biol 32:1h.8.1-1h.8.20

    Article  PubMed  Google Scholar 

  199. Diniz B, Thomas P, Thomas B, Ribeiro R, Hu Y, Brant R, Ahuja A, Zhu D, Liu L, Koss M et al (2013) Subretinal implantation of retinal pigment epithelial cells derived from human embryonic stem cells: improved survival when implanted as a monolayer. Invest Ophthalmol Vis Sci 54:5087–5096

    Article  PubMed  PubMed Central  Google Scholar 

  200. Kamao H, Mandai M, Okamoto S, Sakai N, Suga A et al (2014) Characterization of human induced pluripotent stem cell-derived retinal pigment epithelium cell sheets aiming for clinical application. Stem Cell Rep 2(2):205–218

    Article  CAS  Google Scholar 

  201. Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ et al (2015) Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 385(9967):509–516

    Article  PubMed  Google Scholar 

  202. Cyranoski D (2014) Japanese woman is first recipient of next-generation stem cells. Nature 12

  203. Rowland TJ, Blaschke AJ, Buchholz DE, Hikita ST, Johnson LV et al (2013) Differentiation of human pluripotent stem cells to retinal pigmented epithelium in defined conditions using purified extracellular matrix proteins. J Tissue Eng Regen Med 7(8):642–653

    Article  CAS  PubMed  Google Scholar 

  204. Nasonkin IO, Merbs SL, Lazo K, Oliver VF, Brooks M, Patel K, Enke RA, Nellissery J, Jamrich M, Le YZ et al (2013) Conditional knockdown of DNA methyltransferase 1 reveals a key role of retinal pigment epithelium integrity in photoreceptor outer segment morphogenesis. Development 140:1330–1341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Shadforth AM, George KA, Kwan AS, Chirila TV, Harkin DG (2012) The cultivation of human retinal pigment epithelial cells on Bombyx mori silk fibroin. Biomaterials 33(16):4110–4117

    Article  CAS  PubMed  Google Scholar 

  206. McHugh KJ, Tao SL, Saint-Geniez M (2014) Porous poly(ε-caprolactone) scaffolds for retinal pigment epithelium transplantation. Invest Ophthamol Vis Sci 55:1754–1762

    Article  CAS  Google Scholar 

  207. Croze RH, Clegg DO (2014) Differentiation of pluripotent stem cells into retinal pigmented epithelium. Dev Opthalmol 53:81–96

    Google Scholar 

  208. Lu B, Zhu D, Hinton D, Humayun MS, Tai YC (2012) Mesh-supported submicron parylene-c membranes for culturing retinal pigment epithelial cells. Biomed Microdevices 14(4):659–667

    Article  CAS  PubMed  Google Scholar 

  209. Hu Y, Liu L, Lu B, Zhu D, Ribeiro R et al (2012) A novel approach for subretinal implantation of ultrathin substrates containing stem cell-derived retinal pigment epithelium monolayer. Ophthalmic Res 48(4):186–191

    Article  PubMed  Google Scholar 

  210. Liu Z, Yu N, Holz FG, Yang F, Stanzel BV (2014) Enhancement of retinal pigment epithelial culture characteristics and subretinal space tolerance of scaffolds with 200 nm fiber topography. Biomaterials 35(9):2837–2850

    Article  CAS  PubMed  Google Scholar 

  211. Merodio M, Irache JM, Valamanesh F, Mirshahi M (2002) Ocular disposition and tolerance of ganciclovir-loaded albumin nanoparticles after intravitreal injection in rats. Biomaterials 23(7):1587–1594

    Article  CAS  PubMed  Google Scholar 

  212. Kim JH, Kim MH, Jo DH, Yu YS, Lee TG et al (2011) The inhibition of retinal neovascularization by gold nanoparticles via suppression of VEGFR-2 activation. Biomaterials 32(7):1865–1871

    Article  CAS  PubMed  Google Scholar 

  213. Jo DH, Kim JH, Yu YS, Lee TG, Kim JH (2012) Antiangiogenic effect of silicate nanoparticle on retinal neovascularization induced by vascular endothelial growth factor. Nanomedicine 8(5):784–791

    Article  CAS  PubMed  Google Scholar 

  214. Mitra RN, Merwin MJ, Han Z, Conley SM, Al-Ubaidi MR et al (2014) Yttrium oxide nanoparticles prevent photoreceptor death in a light-damage model of retinal degeneration. Free Radic Biol Med 75:140–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Zhou HY, Hao JL, Wang S, Zheng Y, Zhang WS (2013) Nanoparticles in the ocular drug delivery. Int J Ophthalmol 6(3):390–396

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Koirala A, Makkia RS, Cooper MJ, Naash MI (2011) Nanoparticle-mediated gene transfer specific to retinal pigment epithelial cells. Biomaterials 32(35):9483–9493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Rajala A, Wang Y, Zhu Y, Ranjo-Bishop M, Ma JX et al (2014) Nanoparticle-assisted targeted delivery of eye-specific genes to eyes significantly improves the vision of blind mice in vivo. Nano Lett 14(9):5257–5263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Aukunuru JV, Ayalasomayajula SP, Kompella UB (2003) Nanoparticle formulation enhances the delivery and activity of a vascular endothelial growth factor antisense oligonucleotide in human retinal pigment epithelial cells. J Pharm Pharmacol 55(9):1199–1206

    Article  CAS  PubMed  Google Scholar 

  219. Bourges JL, Gautier SE, Delie F, Bejjani RA, Jeanny JC et al (2003) Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci 44(8):3562–3569

    Article  PubMed  Google Scholar 

  220. Bejjani RA, BenEzra D, Cohen H, Rieger J, Andrieu C et al (2005) Nanoparticles for gene delivery to retinal pigment epithelial cells. Mol Vis 11:124–132

    CAS  PubMed  Google Scholar 

  221. Moshfeghi AA, Peyman GA (2005) Micro- and nanoparticulates. Adv Drug Deliv Rev 57(14):2047–2052

    Article  CAS  PubMed  Google Scholar 

  222. Naash M (2006) Applications of nanotechnology to gene delivery in ophthalmology. Invest Ophthalmol Vis Sci 2006:53

    Google Scholar 

  223. Liu J, Min SH, Chiodo V, Boye SL, Alexander J et al (2006) Linear polyethylenimine-based DNA nanoparticle delivery into mouse retinas. Invest Ophthalmol Vis Sci 47(13):844–844

    Google Scholar 

  224. Xu Q, Kambhampati SP, Kannan RM (2013) Nanotechnology approaches for ocular drug delivery. Middle East Afr J Ophthalmol 20(1):26–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Sakurai E, Ozeki H, Kunou N, Ogura Y (2001) Effect of particle size of polymeric nanospheres on intravitreal kinetics. Ophthalmic Res 33(1):31–36

    Article  CAS  PubMed  Google Scholar 

  226. Sakai T, Kuno N, Takamatsu F, Kimura E, Kohno H et al (2007) Prolonged protective effect of basic fibroblast growth factor-impregnated nanoparticles in royal college of surgeons rats. Invest Ophthalmol Vis Sci 48(7):3381–3387

    Article  PubMed  Google Scholar 

  227. Ideta R, Tasaka F, Jang WD, Nishiyama N, Zhang GD et al (2005) Nanotechnology-based photodynamic therapy for neovascular disease using a supramolecular nanocarrier loaded with a dendritic photosensitizer. Nano Lett 5(12):2426–2431

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

No funding was received for this research.

Author information

Authors and Affiliations

  1. UR Advanced Therapeutics Private Limited, ASPIRE-BioNest, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India

    Ishita Shome, Bhavani S. Kowtharapu & Jaganmohan R. Jangamreddy

  2. Centre de Recherche Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada

    Neethi C. Thathapudi

  3. Department of Ophthalmology and Institute of Biomedical Engineering, Université de Montréal, Montréal, QC, Canada

    Neethi C. Thathapudi

  4. Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, 500046, India

    Bindu Madhav Reddy Aramati

Authors
  1. Ishita Shome
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neethi C. Thathapudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bindu Madhav Reddy Aramati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bhavani S. Kowtharapu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jaganmohan R. Jangamreddy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaganmohan R. Jangamreddy.

Ethics declarations

Conflict of interest

No conflicts of interest. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria, educational grants, participation in speakers’ bureaus, membership, employment, consultancies, stock ownership  or other equity interest and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shome, I., Thathapudi, N.C., Aramati, B.M.R. et al. Stages, pathogenesis, clinical management and advancements in therapies of age-related macular degeneration. Int Ophthalmol 43, 3891–3909 (2023). https://doi.org/10.1007/s10792-023-02767-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10792-023-02767-2

Keywords

Search

Navigation