RT Journal Article T1 Microspheres as intraocular therapeutic tools in chronic diseases of the optic nerve and retina A1 Bravo Osuna, Irene A1 Andrés-Guerrero, Vanessa A1 Arranz-Romera, Alicia A1 Esteban Pérez, Sergio A1 Molina-Martínez, Irene T. A1 Herrero-Vanrell, Rocío AB Pathologies affecting the optic nerve and the retina are one of the major causes of blindness. These diseases include age-related macular degeneration (AMD), diabetic Retinopathy (DR) and glaucoma, among others. Also, there are genetic disorders that affect the retina causing visual impairment. The prevalence of neurodegenerative diseases of the posterior segment are increased as most of them are related with the elderly. Even with the access to different treatments, there are some challenges in managing patients suffering retinal diseases. One of them is the need for frequent interventions. Also, an unpredictable response to therapy has suggested that different pathways may be playing a role in the development of these diseases. The management of these pathologies requires the development of controlled drug delivery systems able to slow the progression of the disease without the need of frequent invasive interventions, typically related with endophthalmitis, retinal detachment, ocular hypertension, cataract, inflammation, and floaters, among other. Biodegradable microspheres are able to encapsulate low molecular weight substances and large molecules such as biotechnological products. Over the last years, a large variety of active substances has been encapsulated in microspheres with the intention of providing neuroprotection of the optic nerve and the retina.The purpose of the present review is to describe the use of microspheres in chronic neurodegenerative diseases affecting the retina and the optic nerve. The advantage of microencapsulation of low molecular weight drugs as well as therapeutic peptides and proteins to be used as neuroprotective strategy is discussed. Also, a new use of the microspheres in the development of animal models of neurodegeneration of the posterior segment is described. PB Elsevier SN 0169-409X YR 2018 FD 2018-02-15 LK https://hdl.handle.net/20.500.14352/13184 UL https://hdl.handle.net/20.500.14352/13184 LA eng NO 1. Tian K, Shibata-Germanos S, Pahlitzsch M, Cordeiro MF. Current perspective of neuroprotection and glaucoma. Clin Ophthalmol. 2015;9:2109-18.2. McGuinness MB, Karahalios A, Finger RP, Guymer RH, Simpson JA. Age-Related Macular Degeneration and Mortality: A Systematic Review and Meta-Analysis. Ophthalmic Epidemiol. 2017:1-12.3. Liew G, Wong VW, Ho IV. Mini Review: Changes in the Incidence of and Progression to Proliferative and Sight-Threatening Diabetic Retinopathy Over the Last 30 Years. Ophthalmic Epidemiol. 2017:1-8.4. Xu H, Chen M, Forrester JV. Para-inflammation in the aging retina. Prog Retin Eye Res. 2009;28(5):348-68.5. Herrero-Vanrell R, Bravo-Osuna I, Andres-Guerrero V, Vicario-de-la-Torre M, Molina-Martinez IT. The potential of using biodegradable microspheres in retinal diseases and other intraocular pathologies. Prog Retin Eye Res. 2014;42:27-43.6. Rowe-Rendleman CL, Durazo SA, Kompella UB, Rittenhouse KD, Di Polo A, Weiner AL, et al. Drug and gene delivery to the back of the eye: from bench to bedside. Invest Ophthalmol Vis Sci. 2014;55(4):2714-30.7. Hussain RM, Ciulla TA. Treatment strategies for refractory diabetic macular edema: switching anti-VEGF treatments, adopting corticosteroid-based treatments, and combination therapy. Expert Opin Biol Ther. 2016;16(3):365-74.8. Bravo-Osuna I, Andres-Guerrero V, Pastoriza Abal P, Molina-Martinez IT, Herrero-Vanrell R. Pharmaceutical microscale and nanoscale approaches for efficient treatment of ocular diseases. Drug Deliv Transl Res. 2016;6(6):686-707.9. Zulliger R, Conley SM, Naash MI. Non-viral therapeutic approaches to ocular diseases: An overview and future directions. J Control Release. 2015;219:471-87.10. Solinis MA, del Pozo-Rodriguez A, Apaolaza PS, Rodriguez-Gascon A. Treatment of ocular disorders by gene therapy. Eur J Pharm Biopharm. 2015;95(Pt B):331-42.11. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, 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(2):e106-16.12. Krishnan T, Ravindran RD, Murthy GV, Vashist P, Fitzpatrick KE, Thulasiraj RD, et al. Prevalence of early and late age-related macular degeneration in India: the INDEYE study. Invest Ophthalmol Vis Sci. 2010;51(2):701-7.13. Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012;379(9827):1728-38.14. Khan KN, Mahroo OA, Khan RS, Mohamed MD, McKibbin M, Bird A, et al. Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes. Prog Retin Eye Res. 2016;53:70-106.15. Gupta B, Jyothi S, Sivaprasad S. Current treatment options for retinal angiomatous proliferans (RAP). Br J Ophthalmol. 2010;94(6):672-7.16. Participants VR. Guidelines for using verteporfin (Visudyne) in photodynamic therapy for choroidal neovascularization due to age-related macular degeneration and other causes: update. Retina. 2005;25(2):119-34.17. Wormald R, Evans J, Smeeth L, Henshaw K. Photodynamic therapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2005(4):CD002030.18. Grisanti S, Ziemssen F. Bevacizumab: Off-label use in ophthalmology. Indian Journal of Ophthalmology. 2007;55(6):4.19. Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V. Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci. 2005;46(2):726-33.20. Kaiser PK. Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am J Ophthalmol. 2006;142(4):660-8.21. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-for-service part B claims file. Am J Ophthalmol. 2011;151(5):887-95.e1.22. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-908.23. Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs. 2009;18(10):1573-80.24. Do DV. Antiangiogenic approaches to age-related macular degeneration in the future. Ophthalmology. 2009;116(10 Suppl):S24-6.25. Bourne RR, Stevens GA, White RA, Smith JL, Flaxman SR, Price H, et al. Causes of vision loss worldwide, 1990-2010: a systematic analysis. Lancet Glob Health. 2013;1(6):e339-49.26. Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556-64.27. Liew G, Klein R, Wong TY. The role of genetics in susceptibility to diabetic retinopathy. Int Ophthalmol Clin. 2009;49(2):35-52.28. Abhary S, Hewitt AW, Burdon KP, Craig JE. A systematic meta-analysis of genetic association studies for diabetic retinopathy. Diabetes. 2009;58(9):2137-47.29. Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes. 1997;46(11):1829-39.30. Kern TS. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp Diabetes Res. 2007;2007:95103.31. Nunes S, Pires I, Rosa A, Duarte L, Bernardes R, Cunha-Vaz J. Microaneurysm turnover is a biomarker for diabetic retinopathy progression to clinically significant macular edema: findings for type 2 diabetics with nonproliferative retinopathy. Ophthalmologica. 2009;223(5):292-7.32. De Venecia G, Davis M, Engerman R. Clinicopathologic correlations in diabetic retinopathy. I. Histology and fluorescein angiography of microaneurysms. Arch Ophthalmol. 1976;94(10):1766-73.33. Kohner EM, Henkind P. Correlation of fluorescein angiogram and retinal digest in diabetic retinopathy. Am J Ophthalmol. 1970;69(3):403-14.34. Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res. 2011;30(5):343-58.35. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329(14):977-86.36. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):703-13.37. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361(1):40-51.38. Mancia G. Effects of intensive blood pressure control in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation. 2010;122(8):847-9.39. Rami HE, Barham R, Sun JK, Silva PS. Evidence-Based Treatment of Diabetic Retinopathy. Semin Ophthalmol. 2016:1-8.40. Dhoot DS, Avery RL. Vascular Endothelial Growth Factor Inhibitors for Diabetic Retinopathy. Curr Diab Rep. 2016;16(12):122.41. Stewart MW. Treatment of diabetic retinopathy: Recent advances and unresolved challenges. World J Diabetes. 2016;7(16):333-41.42. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010;376(9735):124-36.43. Ferrari S, Di Iorio E, Barbaro V, Ponzin D, Sorrentino FS, Parmeggiani F. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011;12(4):238-49.44. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795-809.45. Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, et al. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015;372(20):1887-97.46. Maguire AM, Simonelli F, Pierce EA, Pugh EN, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008;358(21):2240-8.47. Winter JO, Cogan SF, Rizzo JF. Retinal prostheses: current challenges and future outlook. Journal of Biomaterials Science, Polymer Edition. 2007;18(8):1031-55.48. Stingl K, Zrenner E. Electronic approaches to restitute vision in patients with neurodegenerative diseases of the retina. Ophthalmic Res. 2013;50(4):215-20.49. Guadagni V, Novelli E, Piano I, Gargini C, Strettoi E. Pharmacological approaches to retinitis pigmentosa: A laboratory perspective. Prog Retin Eye Res. 2015;48:62-81.50. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262-7.51. European Glaucoma Society. Terminology and guidelines for glaucoma. 4th ed. EGS, editor. Italy: PubliComm; 2014. 197 p.52. Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-13; discussion 829-30.53. Medeiros FA, Weinreb RN, Zangwill LM, Alencar LM, Sample PA, Vasile C, et al. Long-term intraocular pressure fluctuations and risk of conversion from ocular hypertension to glaucoma. Ophthalmology. 2008;115(6):934-40.54. Musch DC, Gillespie BW, Niziol LM, Lichter PR, Varma R, Group CS. Intraocular pressure control and long-term visual field loss in the Collaborative Initial Glaucoma Treatment Study. Ophthalmology. 2011;118(9):1766-73.55. Davis BM, Crawley L, Pahlitzsch M, Javaid F, Cordeiro MF. Glaucoma: the retina and beyond. Acta Neuropathol. 2016;132(6):807-26.56. Cordeiro MF, Migdal C, Bloom P, Fitzke FW, Moss SE. Imaging apoptosis in the eye. Eye (Lond). 2011;25(5):545-53.57. Anderson DR, Hendrickson A. Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve. Invest Ophthalmol. 1974;13(10):771-83.58. Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A. The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res. 2012;31(2):152-81.59. Calkins DJ. Critical pathogenic events underlying progression of neurodegeneration in glaucoma. Prog Retin Eye Res. 2012;31(6):702-19.60. Osborne NN. Mitochondria: Their role in ganglion cell death and survival in primary open angle glaucoma. Exp Eye Res. 2010;90(6):750-7.61. Vecino E, Rodriguez FD, Ruzafa N, Pereiro X, Sharma SC. Glia-neuron interactions in the mammalian retina. Prog Retin Eye Res. 2016;51:1-40.62. Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006;58(11):1131-5.63. Ramazani F, Chen W, van Nostrum CF, Storm G, Kiessling F, Lammers T, et al. Strategies for encapsulation of small hydrophilic and amphiphilic drugs in PLGA microspheres: State-of-the-art and challenges. Int J Pharm. 2016;499(1-2):358-67.64. Del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems. A shift to the posterior segment. Drug Discov Today. 2008;13(3-4):135-43.65. Klein R, Klein BE. The prevalence of age-related eye diseases and visual impairment in aging: current estimates. Invest Ophthalmol Vis Sci. 2013;54(14):ORSF5-ORSF13.66. Mansoor S, Kuppermann BD, Kenney MC. Intraocular sustained-release delivery systems for triamcinolone acetonide. Pharm Res. 2009;26(4):770-84.67. Kwak HW, D'Amico DJ. Evaluation of the retinal toxicity and pharmacokinetics of dexamethasone after intravitreal injection. Arch Ophthalmol. 1992;110(2):259-66.68. Hou H, Wang C, Nan K, Freeman WR, Sailor MJ, Cheng L. Controlled Release of Dexamethasone From an Intravitreal Delivery System Using Porous Silicon Dioxide. Invest Ophthalmol Vis Sci. 2016;57(2):557-66.69. Andrés-Guerrero V, Zong M, Ramsay E, Rojas B, Sarkhel S, Gallego B, et al. Novel biodegradable polyesteramide microspheres for controlled drug delivery in Ophthalmology. J Control Release. 2015;211:105-17.70. Cáceres-del-Carpio J, Costa RD, Haider A, Narayanan R, Kuppermann BD. Corticosteroids: Triamcinolone, Dexamethasone and Fluocinolone. Dev Ophthalmol. 2016;55:221-31.71. Cardillo JA, Souza-Filho AA, Oliveira AG. Intravitreal Bioerudivel sustained-release triamcinolone microspheres system (RETAAC). Preliminary report of its potential usefulnes for the treatment of diabetic macular edema. Arch Soc Esp Oftalmol. 2006;81(12):675-7, 9-81.72. Blatsios G, Tzimas AS, Mattheolabakis G, Panagi Z, Avgoustakis K, Gartaganis SP. Development of biodegradable controlled release scleral systems of triamcinolone acetonide. Curr Eye Res. 2010;35(10):916-24.73. Kadam RS, Tyagi P, Edelhauser HF, Kompella UB. Influence of choroidal neovascularization and biodegradable polymeric particle size on transscleral sustained delivery of triamcinolone acetonide. Int J Pharm. 2012;434(1-2):140-7.74. Zarei-Ghanavati S, Malaekeh-Nikouei B, Pourmazar R, Seyedi S. Preparation, characterization, and in vivo evaluation of triamcinolone acetonide microspheres after intravitreal administration. J Ocul Pharmacol Ther. 2012;28(5):502-6.75. Bandi N, Kompella UB. Budesonide reduces vascular endothelial growth factor secretion and expression in airway (Calu-1) and alveolar (A549) epithelial cells. Eur J Pharmacol. 2001;425(2):109-16.76. Kompella UB, Bandi N, Ayalasomayajula SP. Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci. 2003;44(3):1192-201.77. Ayalasomayajula SP, Amrite AC, Kompella UB. Inhibition of cyclooxygenase-2, but not cyclooxygenase-1, reduces prostaglandin E2 secretion from diabetic rat retinas. Eur J Pharmacol. 2004;498(1-3):275-8.78. Saishin Y, Takahashi K, Melia M, Vinores SA, Campochiaro PA. Inhibition of protein kinase C decreases prostaglandin-induced breakdown of the blood-retinal barrier. J Cell Physiol. 2003;195(2):210-9.79. Derevjanik NL, Vinores SA, Xiao WH, Mori K, Turon T, Hudish T, et al. Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest Ophthalmol Vis Sci. 2002;43(7):2462-7.80. Ayalasomayajula SP, Kompella UB. Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model. Eur J Pharmacol. 2003;458(3):283-9.81. Kammerl MC, Debler J, Riegger GA, Krämer BK. COX-2 inhibitors and risk of heart failure. Lancet. 2004;364(9444):1486-7; author reply 7.82. Amrite AC, Ayalasomayajula SP, Cheruvu NP, Kompella UB. Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Invest Ophthalmol Vis Sci. 2006;47(3):1149-60.83. Nadal-Nicolás FM, Rodriguez-Villagra E, Bravo-Osuna I, Sobrado-Calvo P, Molina-Martínez I, Villegas-Pérez MP, et al. Ketorolac Administration Attenuates Retinal Ganglion Cell Death After Axonal Injury. Invest Ophthalmol Vis Sci. 2016;57(3):1183-92.84. Van Gelder RN. Photochemical approaches to vision restoration. Vision Res. 2015;111(Pt B):134-41.85. Groynom R, Shoffstall E, Wu LS, Kramer RH, Lavik EB. Controlled release of photoswitch drugs by degradable polymer microspheres. J Drug Target. 2015;23(7-8):710-5.86. Sinha VR, Trehan A. Biodegradable microspheres for protein delivery. J Control Release. 2003;90(3):261-80.87. Bilati U, Allemann E, Doelker E. Strategic approaches for overcoming peptide and protein instability within biodegradable nano- and microparticles. Eur J Pharm Biopharm. 2005;59(3):375-88.88. van de Weert M, Hennink WE, Jiskoot W. Protein instability in poly(lactic-co-glycolic acid) microparticles. Pharm Res. 2000;17(10):1159-67.89. Al Haushey L, Bolzinger MA, Bordes C, Gauvrit JY, Briancon S. Improvement of a bovine serum albumin microencapsulation process by screening design. Int J Pharm. 2007;344(1-2):16-25.90. Blanco D, Alonso MJ. Protein encapsulation and release from poly(lactide-coglycolide) microspheres: effect of the protein and polymer properties and of the co-encapsulation of surfactant. Eur J Pharm Biopharm. 1998;45.91. Garbayo E, Ansorena E, Lanciaego JL, Aymerich MS, Blanco-Prieto MJ. Sustained release of bioactive glycosylated glial cell-line derived neurotrophic factor from biodegradable polymeric microspheres. Eur J Pharm Biopharm. 2008;69.92. Garbayo E, Montero-Menei CN, Ansorena E, Lanciego JL, Aymerich MS, Blanco-Prieto MJ. Effective GDNF brain delivery using microspheres a promising strategy for Parkinson's disease. J Control Release. 2009;135.93. Tobío M, Nolley J, Guo Y, Mclver J, Alonso MJ. A novel system based on a poloxamer PLGA blend as a tetanus toxoid delivery vehicle. Pharm Res. 1999;16.94. Leach WT, Simpson DT, Val TN, Anuta EC, Yu ZS, Williams RO, et al. Uniform encapsulation of stable protein nanoparticles produced by spray freezing for the reduction of burst release. J Pharm Sci. 2005;94.95. Yuan W, Wu F, Guo M, Jin T. Development of protein delivery microsphere system by a novel S/O/O/W multi-emulsion. Eur J Pharm Sci. 2009;36.96. Han Y, Tian H, He P, Chen X, Jing X. Insulin nanoparticles preparation and encapsulation into poly(lactic-co-glycolic acid) microspheres by using an anhydrous system. Int J Pharm. 2009;378.97. Morita T, Sakamura Y, Horikiri Y, Suzuki T, Yoshino H. Protein encapsulation into biodegradable microspheres by a novel S/O/W emulsion method using poly (ethylene glycol) as a protein micronization adjuvant. J Control Release. 2000;69.98. Koennings S, Sapin A, Blunk T, Menei P, Goepferich A. Towards controlled release of BDNF manufacturing strategies for protein-loaded lipid implants and biocompatibility evaluation in the brain. J Control Release. 2007;119.99. Yandrapu SK, Upadhyay AK, Petrash JM, Kompella UB. Nanoparticles in porous microparticles prepared by supercritical infusion and pressure quench technology for sustained delivery of bevacizumab. Mol Pharm. 2013;10(12):4676-86.100. Li F, Hurley B, Liu Y, Leonard B, Griffith M. Controlled release of bevacizumab through nanospheres for extended treatment of age-related macular degeneration. Open Ophthalmol J. 2012;6:54-8.101. Elsaid N, Jackson TL, Elsaid Z, Alqathama A, Somavarapu S. PLGA Microparticles Entrapping Chitosan-Based Nanoparticles for the Ocular Delivery of Ranibizumab. Mol Pharm. 2016;13(9):2923-40.102. Moreno MR, Tabitha TS, Nirmal J, Radhakrishnan K, Yee CH, Lim S, et al. Study of stability and biophysical characterization of ranibizumab and aflibercept. Eur J Pharm Biopharm. 2016;108:156-67.103. Ye Z, Ji YL, Ma X, Wen JG, Wei W, Huang SM. Pharmacokinetics and distributions of bevacizumab by intravitreal injection of bevacizumab-PLGA microspheres in rabbits. Int J Ophthalmol. 2015;8(4):653-8.104. Zhang L, Si T, Fischer AJ, Letson A, Yuan S, Roberts CJ, et al. Coaxial Electrospray of Ranibizumab-Loaded Microparticles for Sustained Release of Anti-VEGF Therapies. PLoS One. 2015;10(8):e0135608.105. Thanos C, Emerich D. Delivery of neurotrophic factors and therapeutic proteins for retinal diseases. Expert Opin Biol Ther. 2005;5(11):1443-52.106. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260(5111):1130-2.107. Chen ZY, He ZY, He C, Lu CL, Wu XF. Human glial cell-line-derived neurotrophic factor: a structure-function analysis. Biochem Biophys Res Commun. 2000;268(3):692-6.108. Bohn MC, Kozlowski DA, Connor B. Glial cell line-derived neurotrophic factor (GDNF) as a defensive molecule for neurodegenerative disease: a tribute to the studies of antonia vernadakis on neuronal-glial interactions. Int J Dev Neurosci. 2000;18(7):679-84.109. Baltmr A, Duggan J, Nizari S, Salt TE, Cordeiro MF. Neuroprotection in glaucoma - Is there a future role? Exp Eye Res. 2010;91(5):554-66.110. Walton KM. GDNF: a novel factor with therapeutic potential for neurodegenerative disorders. Mol Neurobiol. 1999;19(1):43-59.111. Campos C, Rocha NB, Lattari E, Paes F, Nardi AE, Machado S. Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors. Expert Rev Neurother. 2016;16(6):723-34.112. Sullivan AM, O'Keeffe GW. Neurotrophic factor therapy for Parkinson's disease: past, present and future. Neural Regen Res. 2016;11(2):205-7.113. Budni J, Bellettini-Santos T, Mina F, Garcez ML, Zugno AI. The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease. Aging Dis. 2015;6(5):331-41.114. Read SP, Cashman SM, Kumar-Singh R. POD nanoparticles expressing GDNF provide structural and functional rescue of light-induced retinal degeneration in an adult mouse. Mol Ther. 2010;18(11):1917-26.115. Yang PB, Seiler MJ, Aramant RB, Yan F, Mahoney MJ, Kitzes LM, et al. Trophic factors GDNF and BDNF improve function of retinal sheet transplants. Exp Eye Res. 2010;91(5):727-38.116. Checa-Casalengua P, Jiang C, Bravo-Osuna I, Tucker BA, Molina-Martinez IT, Young MJ, et al. Retinal ganglion cells survival in a glaucoma model by GDNF/Vit E PLGA microspheres prepared according to a novel microencapsulation procedure. J Control Release. 2011;156(1):92-100.117. Osanai M, Nishikiori N, Lee GH, Sawada N. Emerging novel treatment strategies for diabetic eye diseases. Curr Diabetes Rev. 2010;6(1):35-41.118. Frasson M, Picaud S, Leveillard T, Simonutti M, Mohand-Said S, Dreyfus H, et al. Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse. Invest Ophthalmol Vis Sci. 1999;40(11):2724-34.119. Koeberle PD, Ball AK. Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res. 1998;38(10):1505-15.120. Yan Q, Wang J, Matheson CR, Urich JL. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of axotomized retinal ganglion cells in adult rats:comparison to and combination with brain-derived neurotrophic factor (BDNF). J Neurobiol. 1999;38(3):382-90.121. Kyhn MV, Klassen H, Johansson UE, Warfvinge K, Lavik E, Kiilgaard JF, et al. Delayed administration of glial cell line-derived neurotrophic factor (GDNF) protects retinal ganglion cells in a pig model of acute retinal ischemia. Exp Eye Res. 2009;89(6):1012-20.122. Andrieu-Soler C, Aubert-Pouessel A, Doat M, Picaud S, Halhal M, Simonutti M, et al. Intravitreous injection of PLGA microspheres encapsulating GDNF promotes the survival of photoreceptors in the rd1/rd1 mouse. Mol Vis. 2005;11:1002-11.123. Ward MS, Khoobehi A, Lavik EB, Langer R, Young MJ. Neuroprotection of retinal ganglion cells in DBA/2J mice with GDNF-loaded biodegradable microspheres. J Pharm Sci-Us. 2007;96(3):558-68.124. Jiang C, Moore MJ, Zhang X, Klassen H, Langer R, Young M. Intravitreal injections of GDNF-loaded biodegradable microspheres are neuroprotective in a rat model of glaucoma. Mol Vis. 2007;13:1783-92.125. Checa-Casalengua P, Jiang C, Bravo-Osuna I, Tucker BA, Molina-Martinez IT, Young MJ, et al. Preservation of biological activity of glial cell line-derived neurotrophic factor (GDNF) after microencapsulation and sterilization by gamma irradiation. Int J Pharm. 2012;436(1-2):545-54.126. Yao J, Tucker BA, Zhang X, Checa-Casalengua P, Herrero-Vanrell R, Young MJ. Robust cell integration from co-transplantation of biodegradable MMP2-PLGA microspheres with retinal progenitor cells. Biomaterials. 2011;32(4):1041-50.127. Marti HH. Erythropoietin and the hypoxic brain. J Exp Biol. 2004;207(Pt 18):3233-42.128. Rong X, Mo X, Ren T, Yang S, Yuan W, Dong J, et al. Neuroprotective effect of erythropoietin-loaded composite microspheres on retinal ganglion cells in rats. Eur J Pharm Sci. 2011;43(4):334-42.129. Wang Y, Zhang H, Liu Y, Li P, Cao Z, Cao Y. Erythropoietin (EPO) protects against high glucose-induced apoptosis in retinal ganglional cells. Cell Biochem Biophys. 2015;71(2):749-55.130. Rong X, Yang S, Miao H, Guo T, Wang Z, Shi W, et al. Effects of erythropoietin-dextran microparticle-based PLGA/PLA microspheres on RGCs. Invest Ophthalmol Vis Sci. 2012;53(10):6025-34.131. Rong X, Yuan W, Lu Y, Mo X. Safety evaluation of poly(lactic-co-glycolic acid)/poly(lactic-acid) microspheres through intravitreal injection in rabbits. Int J Nanomedicine. 2014;9:3057-68.132. Shmueli RB, Ohnaka M, Miki A, Pandey NB, Lima e Silva R, Koskimaki JE, et al. Long-term suppression of ocular neovascularization by intraocular injection of biodegradable polymeric particles containing a serpin-derived peptide. Biomaterials. 2013;34(30):7544-51.133. Chen YS, Green CR, Wang K, Danesh-Meyer HV, Rupenthal ID. Sustained intravitreal delivery of connexin43 mimetic peptide by poly(D,L-lactide-co-glycolide)acid micro- and nanoparticles--Closing the gap in retinal ischaemia. Eur J Pharm Biopharm. 2015;95(Pt B):378-86.134. Isiegas C, Marinich-Madzarevich JA, Marchena M, Ruiz JM, Cano MJ, de la Villa P, et al. Intravitreal Injection of Proinsulin-Loaded Microspheres Delays Photoreceptor Cell Death and Vision Loss in the rd10 Mouse Model of Retinitis Pigmentosa. Invest Ophthalmol Vis Sci. 2016;57(8):3610-8.135. Corrochano S, Barhoum R, Boya P, Arroba AI, Rodriguez-Muela N, Gomez-Vicente V, et al. Attenuation of vision loss and delay in apoptosis of photoreceptors induced by proinsulin in a mouse model of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2008;49(9):4188-94.136. Punzo C, Kornacker K, Cepko CL. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci. 2009;12(1):44-52.137. Gargini C, Terzibasi E, Mazzoni F, Strettoi E. Retinal organization in the retinal degeneration 10 (rd10) mutant mouse: a morphological and ERG study. J Comp Neurol. 2007;500(2):222-38.138. Kimura H, Spee C, Sakamoto T, Hinton DR, Ogura Y, Tabata Y, et al. Cellular response in subretinal neovascularization induced by bFGF-impregnated microspheres. Invest Ophthalmol Vis Sci. 1999;40(2):524-8.139. Cleland JL, Duenas ET, Park A, Daugherty A, Kahn J, Kowalski J, et al. Development of poly-(D,L-lactide--coglycolide) microsphere formulations containing recombinant human vascular endothelial growth factor to promote local angiogenesis. J Control Release. 2001;72(1-3):13-24.140. Agarwal A, Parriott J, Demirel S, Argo C, Sepah YJ, Do DV, et al. Nonbiological pharmacotherapies for the treatment of diabetic macular edema. Expert Opin Pharmacother. 2015;16(17):2625-35.141. Villegas VM, Aranguren LA, Kovach JL, Schwartz SG, Flynn HW, Jr. Current advances in the treatment of neovascular age-related macular degeneration. Expert Opin Drug Deliv. 2017;14(2):273-82.142. Rezar-Dreindl S, Eibenberger K, Buehl W, Georgopoulos M, Weigert G, Krall C, et al. Role of Additional Dexamethasone for the Management of Persistent or Recurrent Neovascular Age-Related Macular Degeneration under Ranibizumab Treatment. Retina. 2016.143. Wygledowska-Promienska D, Piotrowska-Gwozdz A, Piotrowska-Seweryn A, Mazur-Piotrowska G. Combination of Aflibercept and Bromfenac Therapy in Age-Related Macular Degeneration: A Pilot Study Aflibercept and Bromfenac in AMD. Med Sci Monit. 2015;21:3906-12.144. Osswald CR, Kang-Mieler JJ. Controlled and Extended In Vitro Release of Bioactive Anti-Vascular Endothelial Growth Factors from a Microsphere-Hydrogel Drug Delivery System. Curr Eye Res. 2016;41(9):1216-22. NO Ministerio de Economía y Competitividad (MINECO) NO Instituto de Salud Carlos III/FEDER NO Universidad Complutense de Madrid NO Ministerio de Sanidad, Consumo y Bienestar Social DS Docta Complutense RD 29 abr 2024