{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T04:45:39Z","timestamp":1790484339655,"version":"4.1.0"},"reference-count":59,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T00:00:00Z","timestamp":1554336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory agents. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. Changes in the correct visual acuity and reduction in geographic atrophy progression were evaluated. Several new drugs have shown promising results, including those targeting the complement cascade and neuroprotective agents. The potential action of the two groups of drugs is to block complement cascade upregulation of immunomodulating agents, and to prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. Our analysis indicates that finding treatments for dry AMD will require continued collaboration among researchers to identify additional molecular targets and to fully interrogate the utility of pluripotent stem cells for personalized therapy.<\/jats:p>","DOI":"10.3390\/ijms20071693","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T11:31:57Z","timestamp":1554377517000},"page":"1693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5512-0849","authenticated-orcid":false,"given":"Marcella","family":"Nebbioso","sequence":"first","affiliation":[{"name":"Department of Sense Organs, Faculty of Medicine and Odontology, Umberto I Policlinic, Sapienza University of Rome, p. le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8974-991X","authenticated-orcid":false,"given":"Alessandro","family":"Lambiase","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Faculty of Medicine and Odontology, Umberto I Policlinic, Sapienza University of Rome, p. le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Cerini","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Faculty of Medicine and Odontology, Umberto I Policlinic, Sapienza University of Rome, p. le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Giuseppe","family":"Limoli","sequence":"additional","affiliation":[{"name":"Low Vision Research Centre of Milan, Piazza Sempione 3, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4121-7682","authenticated-orcid":false,"given":"Maurizio","family":"La Cava","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Faculty of Medicine and Odontology, Umberto I Policlinic, Sapienza University of Rome, p. le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4824-9871","authenticated-orcid":false,"given":"Antonio","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Sense Organs, Faculty of Medicine and Odontology, Umberto I Policlinic, Sapienza University of Rome, p. le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"ref_2","first-page":"508","article-title":"New treatment modalities for geographic atrophy","volume":"6","author":"Kandasamy","year":"2017","journal-title":"Asia Pac. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.ophtha.2013.11.023","article-title":"Geographic atrophy: Clinical features and potential therapeutic approaches","volume":"121","author":"Holz","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3928\/23258160-20150101-01","article-title":"Geographic atrophy: Clinical impact and emerging treatments","volume":"46","author":"Patel","year":"2015","journal-title":"Ophthalmic Surg. Lasers Imaging Retina"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1001\/jamaophthalmol.2013.6636","article-title":"Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study: AREDS report no. 36","volume":"132","author":"Chew","year":"2014","journal-title":"JAMA Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e965","DOI":"10.1038\/cddis.2013.478","article-title":"Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells","volume":"4","author":"Hanus","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2008.10.001","article-title":"Molecular pathology of age-related macular degeneration","volume":"28","author":"Ding","year":"2009","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/eye.2010.196","article-title":"The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment","volume":"25","author":"Wang","year":"2011","journal-title":"Eye"},{"key":"ref_9","first-page":"133","article-title":"The role of the complement system in age-related macular degeneration","volume":"111","author":"Weber","year":"2014","journal-title":"Dtsch. Arztebl. Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1136\/bjophthalmol-2015-306972","article-title":"Current therapeutic developments in atrophic age-related macular degeneration","volume":"100","author":"Hanus","year":"2016","journal-title":"Br. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1080\/13543784.2017.1369042","article-title":"Current drug and molecular therapies for the treatment of atrophic age-related macular degeneration: Phase I to phase III clinical development","volume":"26","author":"Li","year":"2017","journal-title":"Expert Opin. Investig. Drugs."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/10408398.2014.893504","article-title":"Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review","volume":"57","author":"Nebbioso","year":"2017","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2514","DOI":"10.1038\/cddis.2016.397","article-title":"Non-amyloidogenic effects of \u03b12 adrenergic agonists: Implications for brimonidine-mediated neuroprotection","volume":"7","author":"Nizari","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"209","DOI":"10.4103\/2008-322X.183923","article-title":"Neuroprotection in Glaucoma","volume":"11","author":"Doozandeh","year":"2016","journal-title":"J. Ophthalmic Vis. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6241","DOI":"10.1073\/pnas.1018987108","article-title":"Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration","volume":"108","author":"Zhang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4652","DOI":"10.1073\/pnas.061034298","article-title":"Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity","volume":"98","author":"Lambert","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1089\/ten.2004.10.1617","article-title":"Sustained secretion of ciliary neurotrophic factor to the vitreous, using the encapsulated cell therapy-based NT-501 intraocular device","volume":"10","author":"Thanos","year":"2004","journal-title":"Tissue Eng."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7484","DOI":"10.1167\/iovs.12-9970","article-title":"Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases","volume":"53","author":"Kauper","year":"2012","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/IAE.0b013e3182979ddd","article-title":"A phase ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy. Phase Ia Investigators","volume":"34","author":"Do","year":"2014","journal-title":"Retina"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eaaf1443","DOI":"10.1126\/scitranslmed.aaf1443","article-title":"Targeting factor D of the alternative complement pathway reduces geographic atrophyprogression secondary to age-related macular degeneration. MAHALO Study Investigators","volume":"9","author":"Yaspan","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1001\/jamaophthalmol.2018.1544","article-title":"Efficacy and Safety of Lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials","volume":"136","author":"Holz","year":"2018","journal-title":"JAMA Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.ophtha.2014.08.035","article-title":"Outer retinal tubulation as a predictor of the enlargement amount of geographic atrophy in age-related macular degeneration","volume":"122","author":"Hariri","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e10422","DOI":"10.1097\/MD.0000000000010422","article-title":"Therapeutic effects of various therapeutic strategies on non-exudative age-related macular degeneration: A PRISMA-compliant network meta-analysis of randomized controlled trials","volume":"97","author":"Wei","year":"2018","journal-title":"Medicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1089\/nat.2015.0573","article-title":"Fit for the Eye: Aptamers in Ocular Disorders","volume":"26","author":"Drolet","year":"2016","journal-title":"Nucleic Acid Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11959","DOI":"10.3390\/molecules200711959","article-title":"A Highlight of recent advances in aptamer technology and its application","volume":"20","author":"Sun","year":"2015","journal-title":"Molecules"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kassa, E., Ciulla, T.A., Hussain, R.M., and Dugel, P.U. (2019). Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin. Biol. Ther.","DOI":"10.1080\/14712598.2019.1575358"},{"key":"ref_27","first-page":"5010","article-title":"ASaP Study Group. Complement C3 inhibitor POT-4: Clinical Safety of Intravitreal Administration","volume":"50","author":"Kaushal","year":"2009","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"29","DOI":"10.12703\/P6-29","article-title":"Advances in the management of macular degeneration","volume":"6","author":"Singer","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.smim.2016.06.001","article-title":"New milestones ahead in complement-targeted therapy","volume":"28","author":"Ricklin","year":"2016","journal-title":"Semin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sagar, A., Dai, W., Minot, M., LeCover, R., and Varner, J.D. (2017). Reduced order modeling and analysis of the human complement system. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187373"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.4103\/0974-9233.173134","article-title":"Update on clinical trials in dry age-related macular degeneration","volume":"23","author":"Taskintuna","year":"2016","journal-title":"Middle East Afr. J. Ophthalmol."},{"key":"ref_32","first-page":"2029","article-title":"Topline results from a prospective, double-masked, placebo-controlled phase-2b clinical study evaluating ALG-1001 (Luminate) in patients with diabetic macular edema","volume":"58","author":"Kaiser","year":"2017","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_33","unstructured":"(2017, March 29). Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/results\/NCT03144999."},{"key":"ref_34","unstructured":"(2017, September 21). Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03295877."},{"key":"ref_35","first-page":"2143","article-title":"Side-effect profile of brimonidine tartrate in children","volume":"112","author":"Turkmani","year":"2005","journal-title":"Ophthalmology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1001\/archophthalmol.2009.9","article-title":"Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: An evidence-based review","volume":"127","author":"Saylor","year":"2009","journal-title":"Arch Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/cne.10701","article-title":"Distribution of CNTF receptor alpha protein in the central nervous system of the chick embryo","volume":"461","author":"Fuhrmann","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"ref_38","first-page":"3292","article-title":"Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa","volume":"43","author":"Tao","year":"2002","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kimura, A., Namekata, K., Guo, X., Harada, C., and Harada, T. (2016). Neuroprotection, growth factors and BDNF-TrkB signalling in retinal degeneration. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091584"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/B978-1-4557-0737-9.00067-9","article-title":"Pharmacotherapy of Age-Related Macular Degeneration","volume":"67","author":"Blumenkranz","year":"2013","journal-title":"Retina"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1097\/IAE.0000000000001392","article-title":"The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target","volume":"37","author":"Boyer","year":"2017","journal-title":"Retina"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ejpb.2015.02.020","article-title":"Antibody therapies and their challenges in the treatment of age-related macular degeneration","volume":"95","author":"Volz","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0008-4182(04)80054-1","article-title":"Age-related changes in the human retina","volume":"39","author":"Cavallotti","year":"2004","journal-title":"Can. J. Ophthalmol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1177\/0394632015615592","article-title":"Age and diabetes related changes of the retinal capillaries: An ultrastructural and immunohistochemical study","volume":"29","author":"Bianchi","year":"2016","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"671529","DOI":"10.1155\/2014\/671529","article-title":"Scotopic microperimetry in the early diagnosis of age-related macular degeneration: Preliminary study","volume":"2014","author":"Nebbioso","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ophtha.2017.08.038","article-title":"The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration","volume":"125","author":"Fleckenstein","year":"2018","journal-title":"Ophthalmology."},{"key":"ref_47","unstructured":"World Health Organization (WHO) (2017, February 02). ICD-10 Version: 2016. Available online: http:\/\/apps.who.int\/classifications\/icd10\/browse\/2016\/en#\/H35."},{"key":"ref_48","unstructured":"Centers for Disease Control (CDC) (2017, February 08). International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM): 2016 Version, Available online: https:\/\/www.cdc.gov\/nchs\/icd\/icd10cm.htm."},{"key":"ref_49","unstructured":"World Health Organization (WHO) (2017, February 02). ICD-11 Beta Draft (Mortality and Morbidity Statistics). Available online: http:\/\/id.who.int\/icd\/entity\/627268703."},{"key":"ref_50","unstructured":"American Academy of Ophthalmology (AAO) (2017, February 02). ICD10-CM: Subspecialty ICD-10 Decision Trees and Guides; 2016. Available online: https:\/\/www.aao.org\/practice-management\/coding\/icd-10-cm."},{"key":"ref_51","unstructured":"Centers for Disease Control (CDC) (2017, February 08). International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM): 2017 Version, Available online: https:\/\/www.cdc.gov\/nchs\/icd\/icd10cm.htm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ophtha.2016.12.002","article-title":"Imaging protocols in clinical studies in advanced age-related macular degeneration: Recommendations from classification of atrophy consensus meetings","volume":"124","author":"Holz","year":"2017","journal-title":"Ophthalmology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1590\/S0021-25712009000400014","article-title":"Nerve growth factor eye drops improve visual acuity and electrofunctional activity in age-related macular degeneration: A case report","volume":"45","author":"Lambiase","year":"2009","journal-title":"Ann. Ist. Super. Sanit\u00e0."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e355","DOI":"10.1097\/MD.0000000000000355","article-title":"Preliminary study on electrophysiological changes after cellular autograft in age-related macular degeneration","volume":"93","author":"Limoli","year":"2014","journal-title":"Medicine"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"46913","DOI":"10.18632\/oncotarget.10442","article-title":"Cell surgery and growth factors in dry age-related macular degeneration: Visual prognosis and morphological study","volume":"7","author":"Limoli","year":"2016","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Limoli, P.G., Vingolo, E.M., Limoli, C., Scalinci, S.Z., and Nebbioso, M. (2018). Regenerative therapy by suprachoroidal cell autograft in dry age-related macular degeneration: Preliminary in vivo report. J. Vis. Exp., 132.","DOI":"10.3791\/56469"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S1388-1981(99)00061-X","article-title":"Inositides in the nucleus: Presence and characterisation of the isozymes of phospholipasebeta family in NIH 3T3 cells","volume":"1438","author":"Cocco","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Jha, K.A., Pentecost, M., Lenin, R., Klaic, L., Elshaer, S.L., Gentry, J., Russell, J.M., Beland, A., Reiner, A., and Jotterand, V. (2018). Concentrated conditioned media from adipose tissue derived mesenchymal stem cells mitigates visual deficits and retinal inflammation following mild traumatic brain injury. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072016"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"121","DOI":"10.4103\/jmedsci.jmedsci_115_16","article-title":"Overview of clinical trials for dry age-related macular degeneration","volume":"37","author":"Cheng","year":"2017","journal-title":"J. Med. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1693\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:43:05Z","timestamp":1760186585000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,4]]},"references-count":59,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071693"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071693","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201902.0101.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,4]]}}}