Emerging treatments for dry age-related macular degeneration with geographic atrophy: a systematic review

Authors

  • Alvin Kwan Ho Kwok Dept. of Ophthalmology, HK Sanatorium and Hospital
  • Ho Lam Wong

Keywords:

Cell- and tissue-based therapy, Complement inactivating agents, Dietary supplements, Geographic atrophy, Macular degeneration

Abstract

We aim to summarize various emerging treatments for geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD). The PubMed database was searched using keywords: ‘treatment’ and ‘geographic atrophy’ or ‘dry age-related macular degeneration’ on 19 June 2021. Of 121 articles yielded, 20 relevant clinical studies that were of ‘English language’ and ‘published within 10 years’ were included. The emerging treatments of dry AMD with GA were categorized into complement inhibitors, diet and supplement, cell-based therapies, and pharmacological agents. Complement inhibitors (C3 inhibitor pegcetacoplan, complement factor D, and C5 inhibitors) can significantly reduce the GA lesion area growth, as can Mediterranean diet and α-lipoic acid. Cell-based therapies such as palucorel and biosynthetic retinal pigment epithelium monolayer delivery can minimize GA lesion area and improve the best-corrected visual acuity. Pharmacological agents such as fenretinide, ciliary neurotrophic growth factor, trimetazidine, and brimonidine have prominent effects on GA, but emixustat hydrochloride, tandospirone, and sirolimus lack such effects. The Age-Related Eye Disease Study formulation remains important in reducing the risk of progression of GA secondary to dry AMD. A thorough understanding of the emerging treatment of GA may enable more personalized treatment. Nonetheless, the safety and efficacy of the treatment ought to be tested in trials with larger sample size, longer duration, and optimized dosage.

References

Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet 2018;392:1147-59.

Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1992;99:933-43.

Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2014;2:e106-16.

Mitchell P, Wang JJ, Foran S, Smith W. Five-year incidence of age-related maculopathy lesions: the Blue Mountains Eye Study. Ophthalmology 2002;109:1092-7.

Ejiakor I, Achigbu E, Onyia O, Edema O, Florence UN. Impact of visual impairment and blindness on quality of life of patients in Owerri, Imo State, Nigeria. Middle East Afr J Ophthalmol 2019;26:127-32.

Zajac-Pytrus HM, Pilecka A, Turno-Krecicka A, Adamiec-Mroczek J, Misiuk-Hojlo M. The dry form of age-related macular degeneration (AMD): the current concepts of pathogenesis and prospects for treatment. Adv Clin Exp Med 2015;24:1099-104.

Arya M, Sabrosa AS, Duker JS, Waheed NK. Choriocapillaris changes in dry age-related macular degeneration and geographic atrophy: a review. Eye Vis (Lond) 2018;5:22.

Bandello F, Sacconi R, Querques L, Corbelli E, Cicinelli MV, Querques G. Recent advances in the management of dry age-related macular degeneration: a review. F1000Res 2017;6:245.

Yehoshua Z, Rosenfeld PJ, Albini TA. Current clinical trials in dry AMD and the definition of appropriate clinical outcome measures. Semin Ophthalmol 2011;26:167-80.

Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 2013;309:2005-15.

Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385-9.

Vignesh P, Rawat A, Sharma M, Singh S. Complement in autoimmune diseases. Clin Chim Acta 2017;465:123-30.

Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 2010;29:95-112.

Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology 2020;127:186-95.

Volanakis JE, Narayana SV. Complement factor D, a novel serine protease. Protein Sci 1996;5:553-64.

Yaspan BL, Williams DF, Holz FG, et al. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci Transl Med 2017;9:eaaf1443.

Holz FG, Sadda SR, Busbee B, et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmol 2018;136:666-77.

Heier JS, Pieramici D, Chakravarthy U, et al. Visual function decline resulting from geographic atrophy: results from the Chroma and Spectri phase 3 trials. Ophthalmol Retina 2020;4:673-88.

Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat 2010;31:E1445-60.

Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology 2014;121:693-701.

Li W, Chen S, Ma M, Qian J, Ma X. Complement 5b-9 complex-induced alterations in human RPE cell physiology. Med Sci Monit 2010;16:BR17-23.

Jaffe GJ, Westby K, Csaky KG, et al. C5 Inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology 2021;128:576-86.

Widmer RJ, Flammer AJ, Lerman LO, Lerman A. The Mediterranean diet, its components, and cardiovascular disease. Am J Med 2015;128:229-38.

Dinu M, Pagliai G, Casini A, Sofi F. Mediterranean diet and multiple health outcomes: an umbrella review of meta-analyses of observational studies and randomised trials. Eur J Clin Nutr 2018;72:30-43.

Keenan TD, Agron E, Mares J, et al. Adherence to the Mediterranean diet and progression to late age-related macular degeneration in the Age-Related Eye Disease Studies 1 and 2. Ophthalmology 2020;127:1515-28.

Packer L, Roy S, Sen CK. Alpha-lipoic acid: a metabolic antioxidant and potential redox modulator of transcription. Adv Pharmacol 1997;38:79-101.

Liu J, Ames BN. Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer's disease, and Parkinson's disease. Nutr Neurosci 2005;8:67-89.

Jia L, Liu Z, Sun L, et al. Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-alpha-lipoic acid. Invest Ophthalmol Vis Sci 2007;48:339-48.

Sun YD, Dong YD, Fan R, Zhai LL, Bai YL, Jia LH. Effect of (R)-alpha-lipoic acid supplementation on serum lipids and antioxidative ability in patients with age-related macular degeneration. Ann Nutr Metab 2012;60:293-7.

Kasahara E, Lin LR, Ho YS, Reddy VN. SOD2 protects against oxidation-induced apoptosis in mouse retinal pigment epithelium: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 2005;46:3426-34.

Cao J, Murat C, An W, et al. Human umbilical tissue-derived cells rescue retinal pigment epithelium dysfunction in retinal degeneration. Stem Cells 2016;34:367-79.

Lund RD, Wang S, Lu B, et al. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007;25:602-11.

Ho AC, Chang TS, Samuel M, Williamson P, Willenbucher RF, Malone T. Experience with a subretinal cell-based therapy in patients with geographic atrophy secondary to age-related macular degeneration. Am J Ophthalmol 2017;179:67-80.

Heier JS, Ho AC, Samuel MA, et al. Safety and efficacy of subretinally administered palucorcel for geographic atrophy of age-related macular degeneration: phase 2b study. Ophthalmol Retina 2020;4:384-93.

Schwartz SD, Tan G, Hosseini H, Nagiel A. Subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium for the treatment of macular degeneration: an assessment at 4 years. Invest Ophthalmol Vis Sci 2016;57:ORSFc1-9.

Kashani AH, Uang J, Mert M, et al. Surgical method for implantation of a biosynthetic retinal pigment epithelium monolayer for geographic atrophy: experience from a phase 1/2a study. Ophthalmol Retina 2020;4:264-73.

Petrukhin K. Pharmacological inhibition of lipofuscin accumulation in the retina as a therapeutic strategy for dry AMD treatment. Drug Discov Today Ther Strateg 2013;10:e11-e20.

Rosenfeld PJ, Dugel PU, Holz FG, et al. Emixustat hydrochloride for geographic atrophy secondary to age-related macular degeneration: a randomized clinical trial. Ophthalmology 2018;125:1556-67.

Lin J, Su Y, Wang C, et al. Effects of tandospirone augmentation in major depressive disorder patients with high anxiety: a multicenter, randomized, parallel-controlled, open-label study. J Psychiatr Res 2018;99:104-10.

Bode-Greuel KM, Klisch J, Horvath E, Glaser T, Traber J. Effects of 5-hydroxytryptamine1A-receptor agonists on hippocampal damage after transient forebrain ischemia in the Mongolian gerbil. Stroke 1990;21(12 Suppl):IV164-6.

Collier RJ, Patel Y, Martin EA, et al. Agonists at the serotonin receptor (5-HT1A) protect the retina from severe photo-oxidative stress. Invest Ophthalmol Vis Sci 2011;52:2118-26.

Jaffe GJ, Schmitz-Valckenberg S, Boyer D, et al. Randomized trial to evaluate tandospirone in geographic atrophy secondary to age-related macular degeneration: the GATE Study. Am J Ophthalmol 2015;160:1226-34.

Mody N, McIlroy GD. The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes. Biochem Pharmacol 2014;91:277-86.

Sparrow JR, Zhou J, Ben-Shabat S, Vollmer H, Itagaki Y, Nakanishi K. Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci 2002;43:1222-7.

Mata NL, Lichter JB, Vogel R, Han Y, Bui TV, Singerman LJ. Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. Retina 2013;33:498-507.

Camardo J. The Rapamune era of immunosuppression 2003: the journey from the laboratory to clinical transplantation. Transplant Proc 2003;35(3 Suppl):18S-24S.

Kahan BD. Sirolimus: a comprehensive review. Expert Opin Pharmacother 2001;2:1903-17.

Agarwal A, Rajagopalan N, Hassan M, et al. Sirolimus for retinal and uveitic diseases. Dev Ophthalmol 2016;55:276-81.

Petrou PA, Cunningham D, Shimel K, et al. Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci 2014;56:330-8.

Wong WT, Dresner S, Forooghian F, et al. Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci 2013;54:2941-50.

Fuhrmann S, Kirsch M, Hofmann HD. Ciliary neurotrophic factor promotes chick photoreceptor development in vitro. Development 1995;121:2695-706.

Zhang K, Hopkins JJ, Heier JS, et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A 2011;108:6241-5.

Marzilli M, Vinereanu D, Lopaschuk G, et al. Trimetazidine in cardiovascular medicine. Int J Cardiol 2019;293:39-44.

Cohen SY, Bourgeois H, Corbe C, et al. Randomized clinical trial France DMLA2: effect of trimetazidine on exudative and nonexudative age-related macular degeneration. Retina 2012;32:834-43.

Lusthaus JA, Goldberg I. Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation. Expert Opin Drug Saf 2017;16:1071-8.

Ramírez C, Cáceres-del-Carpio J, Chu J, et al. Brimonidine can prevent in vitro hydroquinone damage on retinal pigment epithelium cells and retinal müller cells. J Ocul Pharmacol Ther 2016;32:102-8.

Kuppermann BD, Patel SS, Boyer DS, et al. Phase 2 study of the safety and efficacy of brimonidine drug delivery system (Brimo DDS) generation 1 in patients with geographic atrophy secondary to age-related macular degeneration. Retina 2021;41:144-55.

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12.

Zhang J, Kiser PD, Badiee M, et al. Molecular pharmacodynamics of emixustat in protection against retinal degeneration. J Clin Invest 2015;125:2781-94.

Downloads

Published

2021-12-15

How to Cite

1.
Kwok AKH, Wong HL. Emerging treatments for dry age-related macular degeneration with geographic atrophy: a systematic review. Hong Kong J Ophthalmol [Internet]. 2021Dec.15 [cited 2022May28];25(2). Available from: https://hkjo.hk/index.php/hkjo/article/view/315

Issue

Section

Review Articles