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Research Article

Human Retinal Pigment Epithelial Cells Overexpressing the Neuroprotective Proteins PEDF and GM-CSF to Treat Degeneration of the Neural Retina

Author(s): Thais Bascuas*, Hajer Zedira, Martina Kropp, Nina Harmening, Mohamed Asrih, Cécile Prat-Souteyrand, Shuwei Tian and Gabriele Thumann

Volume 22, Issue 2, 2022

Published on: 07 July, 2021

Page: [168 - 183] Pages: 16

DOI: 10.2174/1566523221666210707123809

Price: $65

Abstract

Background: Non-viral transposon-mediated gene delivery can overcome viral vectors’ limitations. Transposon gene delivery offers the safe and life-long expression of genes such as Pigment Epithelium-Derived Factor (PEDF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to counteract retinal degeneration by reducing oxidative stress damage.

Objective: The study aimed at using Sleeping Beauty transposon to transfect human Retinal Pigment Epithelial (RPE) cells with the neuroprotective factors PEDF and GM-CSF to investigate the effect of these factors on oxidative stress damage.

Methods: Human RPE cells were transfected with PEDF and GM-CSF by electroporation, using the hyperactive Sleeping Beauty transposon gene delivery system (SB100X). Gene expression was determined by RT-qPCR, and protein level by Western Blot as well as ELISA. The cellular stress level and the neuroprotective effect of the proteins were determined by measuring the concentrations of the antioxidant glutathione in human RPE cells, and conducting immunohistochemical examination of retinal integrity, inflammation, and apoptosis of rat Retina-Organotypic Cultures (ROC) exposed to H2O2.

Results: Human RPE cells were efficiently transfected showing a significantly augmented gene expression and protein secretion. Human RPE cells overexpressing PEDF and/or GM-CSF or pretreated with recombinant proteins presented significantly increased glutathione levels post- H2O2 incubation than non-transfected/untreated controls. rPEDF and/or rGM-CSF-treated ROC exhibited decreased inflammatory reactions and cell degeneration.

Conclusion: GM-CSF and/or PEDF could be delivered successfully to RPE cells with combined use of SB100X and electroporation. PEDF and/or GM-CSF reduced H2O2-mediated oxidative stress damage in RPE cells and ROC offering an encouraging technique to re-establish a cell protective environment to halt age-related retinal degeneration.

Keywords: Sleeping beauty transposon, PEDF, GM-CSF, age-related macular degeneration, RPE cells, non-viral gene delivery, oxidative stress damage, ocular gene therapy.

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[1]
NIH. Available from: https://nei.nih.gov/learn-about-eye-health/resources-for-health-educators/eye-health-data-and-statistics/age-related-macular-degeneration-amd-data-and-statistics [Accessed November 13, 2020]
[2]
Mitchell P, Liew G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet 2018; 392(10153): 1147-59.
[http://dx.doi.org/10.1016/S0140-6736(18)31550-2] [PMID: 30303083]
[3]
Al-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: A review. Clin Interv Aging 2017; 12: 1313-30.
[http://dx.doi.org/10.2147/CIA.S143508] [PMID: 28860733]
[4]
Sacconi R, Corbelli E, Querques L, Bandello F, Querques G. A review of current and future management of geographic atrophy. Ophthalmol Ther 2017; 6(1): 69-77.
[http://dx.doi.org/10.1007/s40123-017-0086-6] [PMID: 28391446]
[5]
Kumar-Singh R. The role of complement membrane attack complex in dry and wet amd - from hypothesis to clinical trials. Exp Eye Res 2019; 184: 266-77.
[http://dx.doi.org/10.1016/j.exer.2019.05.006] [PMID: 31082363]
[6]
Bascuas T, Kropp M, Harmening N, Asrih M, Izsvák Z, Thumann G. Induction and analysis of oxidative stress in sleeping beauty transposon-transfected human retinal pigment epithelial cells. J Vis Exp 2020; 2020(166): 1-25.
[PMID: 33369607]
[7]
He Y, Leung KW, Ren Y, Pei J, Ge J, Tombran-Tink J. PEDF improves mitochondrial function in RPE cells during oxidative stress. Invest Ophthalmol Vis Sci 2014; 55(10): 6742-55.
[http://dx.doi.org/10.1167/iovs.14-14696] [PMID: 25212780]
[8]
Cao S, Walker GB, Wang X, Cui JZ, Matsubara JA. Altered cytokine profiles of human retinal pigment epithelium: Oxidant injury and replicative senescence. Mol Vis 2013; 19: 718-28.
[PMID: 23559866]
[9]
Farnoodian M, Sorenson CM, Sheibani N. PEDF expression affects the oxidative and inflammatory state of choroidal endothelial cells. Am J Physiol Cell Physiol 2018; 314(4): C456-72.
[http://dx.doi.org/10.1152/ajpcell.00259.2017] [PMID: 29351407]
[10]
Polato F, Becerra SP. Retinal degenerative diseases: Mechanisms and experimental therapies. Retinal Degenerative Diseases. 2016; pp. 699-706.
[http://dx.doi.org/10.1007/978-1-4614-3209-8]
[11]
Schallenberg M, Charalambous P, Thanos S. GM-CSF regulates the ERK1/2 pathways and protects injured retinal ganglion cells from induced death. Exp Eye Res 2009; 89(5): 665-77.
[http://dx.doi.org/10.1016/j.exer.2009.06.008] [PMID: 19560459]
[12]
Schallenberg M, Charalambous P, Thanos S. GM-CSF protects rat photoreceptors from death by activating the SRC-dependent signalling and elevating anti-apoptotic factors and neurotrophins. Graefes Arch Clin Exp Ophthalmol 2012; 250(5): 699-712.
[http://dx.doi.org/10.1007/s00417-012-1932-9] [PMID: 22297538]
[13]
Tombran-Tink J, Barnstable CJ. PEDF: A multifaceted neurotrophic factor. Nat Rev Neurosci 2003; 4(8): 628-36.
[http://dx.doi.org/10.1038/nrn1176] [PMID: 12894238]
[14]
Tombran-Tink J. The neuroprotective and angiogenesis inhibitory serpin, PEDF: New insights into phylogeny, function, and signaling. Front Biosci 2005; 10: 2131-49.
[http://dx.doi.org/10.2741/1686] [PMID: 15970483]
[15]
Bilak MM, Corse AM, Bilak SR, Lehar M, Tombran-Tink J, Kuncl RW. Pigment epithelium-derived factor (PEDF) protects motor neurons from chronic glutamate-mediated neurodegeneration. J Neuropathol Exp Neurol 1999; 58(7): 719-28.
[http://dx.doi.org/10.1097/00005072-199907000-00006] [PMID: 10411342]
[16]
Duh EJ, Yang HS, Suzuma I, et al. Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002; 43(3): 821-9.
[PMID: 11867604]
[17]
Gene therapy clinical trials worldwide Available from: http://www.abedia.com/wiley/search.php [Accessed April 19, 2020].
[18]
Hartman ZC, Black EP, Amalfitano A. Adenoviral infection induces a multi-faceted innate cellular immune response that is mediated by the toll-like receptor pathway in A549 cells. Virology 2007; 358(2): 357-72.
[http://dx.doi.org/10.1016/j.virol.2006.08.041] [PMID: 17027060]
[19]
Han IC, Burnight ER, Ulferts MJ, et al. Helper-dependent adenovirus transduces the human and rat retina but elicits an inflammatory reaction when delivered subretinally in rats. Hum Gene Ther 2019; 30(11): 1371-84.
[http://dx.doi.org/10.1089/hum.2019.159] [PMID: 31456426]
[20]
Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral gene therapy vectors. Mol Ther 2020; 28(3): 709-22.
[http://dx.doi.org/10.1016/j.ymthe.2020.01.001] [PMID: 31968213]
[21]
Cavazza A, Moiani A, Mavilio F. Mechanisms of retroviral integration and mutagenesis. Hum Gene Ther 2013; 24(2): 119-31.
[http://dx.doi.org/10.1089/hum.2012.203] [PMID: 23330935]
[22]
Biasco L, Baricordi C, Aiuti A. Retroviral integrations in gene therapy trials. Mol Ther 2012; 20(4): 709-16.
[http://dx.doi.org/10.1038/mt.2011.289] [PMID: 22252453]
[23]
Kuşcu L, Sezer AD. Future prospects for gene delivery systems. Expert Opin Drug Deliv 2017; 14(10): 1205-15.
[http://dx.doi.org/10.1080/17425247.2017.1292248] [PMID: 28165836]
[24]
Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 2008; 118(9): 3132-42.
[http://dx.doi.org/10.1172/JCI35700] [PMID: 18688285]
[25]
Feschotte C, Pritham EJ. DNA transposons and the evolution of eukaryotic genomes. Annu Rev Genet 2007; 41: 331-68.
[http://dx.doi.org/10.1146/annurev.genet.40.110405.090448] [PMID: 18076328]
[26]
Ivics Z, Izsvák Z. The expanding universe of transposon technologies for gene and cell engineering. Mob DNA 2010; 1(1): 25.
[http://dx.doi.org/10.1186/1759-8753-1-25] [PMID: 21138556]
[27]
Yant SR, Meuse L, Chiu W, Ivics Z, Izsvak Z, Kay MA. Somatic integration and long-term transgene expression in normal and haemophilic mice using a DNA transposon system. Nat Genet 2000; 25(1): 35-41.
[http://dx.doi.org/10.1038/75568] [PMID: 10802653]
[28]
Walisko O, Schorn A, Rolfs F, et al. Transcriptional activities of the sleeping beauty transposon and shielding its genetic cargo with insulators. Mol Ther 2008; 16(2): 359-69.
[http://dx.doi.org/10.1038/sj.mt.6300366] [PMID: 18071335]
[29]
Hudecek M, Izsvák Z, Johnen S, Renner M, Thumann G, Ivics Z. Going non-viral: The sleeping beauty transposon system breaks on through to the clinical side. Crit Rev Biochem Mol Biol 2017; 52(4): 355-80.
[http://dx.doi.org/10.1080/10409238.2017.1304354] [PMID: 28402189]
[30]
Zayed H, Izsvák Z, Walisko O, Ivics Z. Development of hyperactive sleeping beauty transposon vectors by mutational analysis. Mol Ther 2004; 9(2): 292-304.
[http://dx.doi.org/10.1016/j.ymthe.2003.11.024] [PMID: 14759813]
[31]
Izsvák Z, Ivics Z, Plasterk RH. Sleeping Beauty, a wide host-range transposon vector for genetic transformation in vertebrates. J Mol Biol 2000; 302(1): 93-102.
[http://dx.doi.org/10.1006/jmbi.2000.4047] [PMID: 10964563]
[32]
Potter H, Heller R. Transfection by electroporation. Curr Protocols Mol Biol. 2018; pp. 9.3.1-9.3.13.
[http://dx.doi.org/10.1002/cpmb.48]
[33]
Shirley SA, Heller R, Heller LC. Electroporation gene therapy, gene therapy of cancer: Translational approaches from preclinical studies to clinical implementation. (3rd),. Elsevier Inc. 2013. [Online]
[http://dx.doi.org/10.2174/156652310791823489]
[34]
Pastor M, Johnen S, Harmening N, et al. The antibiotic-free pfar4 vector paired with the sleeping beauty transposon system mediates efficient transgene delivery in human cells. Mol Ther - Nucleic Acids. 2018; 11: pp. 57-67.
[http://dx.doi.org/10.1016/j.omtn.2017.12.017]
[35]
Johnen S, Djalali-Talab Y, Kazanskaya O, et al. Antiangiogenic and neurogenic activities of sleeping beauty-mediated pedf-transfected rpe cells in vitro and in vivo. Biomed Res Int 2015; 2015: S63845.
[http://dx.doi.org/10.1155/2015/863845] [PMID: 26697494]
[36]
Garcia-Garcia L, Recalde S, Hernandez M, et al. Long-term pedf release in rat iris and retinal epithelial cells after sleeping beauty transposon-mediated gene delivery. Mol Ther - Nucleic Acids 2017; 9: 1-11.
[http://dx.doi.org/10.1016/j.omtn.2017.08.001]
[37]
Thumann G, Harmening N, Prat-Souteyrand C, et al. Engineering of pedf-expressing primary pigment epithelial cells by the sb transposon system delivered by pfar4 plasmids. Mol Ther - Nucleic Acids. 2017; 6: pp. 302-14.
[http://dx.doi.org/10.1016/j.omtn.2017.02.002]
[38]
Kuerten D, Johnen S, Harmening N, Souteyrand G, Walter P, Thumann G. Transplantation of PEDF-transfected pigment epithelial cells inhibits corneal neovascularization in a rabbit model. Graefes Arch Clin Exp Ophthalmol 2015; 253(7): 1061-9.
[http://dx.doi.org/10.1007/s00417-015-2954-x] [PMID: 25690979]
[39]
Mátés L, Chuah MKL, Belay E, et al. Molecular evolution of a novel hyperactive sleeping beauty transposase enables robust stable gene transfer in vertebrates. Nat Genet 2009; 41(6): 753-61.
[http://dx.doi.org/10.1038/ng.343] [PMID: 19412179]
[40]
Johnen S, Izsvák Z, Stöcker M, et al. Sleeping Beauty transposon-mediated transfection of retinal and iris pigment epithelial cells. Invest Ophthalmol Vis Sci 2012; 53(8): 4787-96.
[http://dx.doi.org/10.1167/iovs.12-9951] [PMID: 22729435]
[41]
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)) Method. Methods 2001; 25(4): 402-8.
[http://dx.doi.org/10.1006/meth.2001.1262] [PMID: 11846609]
[42]
Kolacsek O, Krízsik V, Schamberger A, et al. Reliable transgene-independent method for determining sleeping beauty transposon copy numbers. Mob DNA 2011; 2(1): 5.
[http://dx.doi.org/10.1186/1759-8753-2-5] [PMID: 21371313]
[43]
Kaempf S, Johnen S, Salz AK, Weinberger A, Walter P, Thumann G. Effects of bevacizumab (Avastin) on retinal cells in organotypic culture. Invest Ophthalmol Vis Sci 2008; 49(7): 3164-71.
[http://dx.doi.org/10.1167/iovs.07-1265] [PMID: 18344448]
[44]
Kaempf S, Walter P, Salz AK, Thumann G. Novel organotypic culture model of adult mammalian neurosensory retina in co-culture with retinal pigment epithelium. J Neurosci Methods 2008; 173(1): 47-58.
[http://dx.doi.org/10.1016/j.jneumeth.2008.05.018] [PMID: 18632159]
[45]
Hurst J, Kuehn S, Jashari A, et al. A novel porcine ex vivo retina culture model for oxidative stress induced by H2O2. Altern Lab Anim 2017; 45(1): 11-25.
[http://dx.doi.org/10.1177/026119291704500105] [PMID: 28409994]
[46]
Geurts AM, Hackett CS, Bell JB, et al. Structure-based prediction of insertion-site preferences of transposons into chromosomes. Nucleic Acids Res 2006; 34(9): 2803-11.
[http://dx.doi.org/10.1093/nar/gkl301] [PMID: 16717285]
[47]
Kebriaei P, Izsvák Z, Narayanavari SA, Singh H, Ivics Z. Gene therapy with the sleeping beauty transposon system. Trends Genet 2017; 33(11): 852-70.
[http://dx.doi.org/10.1016/j.tig.2017.08.008] [PMID: 28964527]
[48]
Yant SR, Wu X, Huang Y, Garrison B, Burgess SM, Kay MA. High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 2005; 25(6): 2085-94.
[http://dx.doi.org/10.1128/MCB.25.6.2085-2094.2005] [PMID: 15743807]
[49]
Bolhassani A, Khavari A, Oraf Z. Electroporation – In: advantages and drawbacks for delivery of drug, gene and vaccine. Application of Nanotechnology in Drug Delivery UK: Intech Open. 2014; pp. 369-98.
[http://dx.doi.org/10.5772/58376]
[50]
NIH. Available from: ClinicalTrials.gov [Accessed November 05, 2020]
[51]
Mashel TV, Tarakanchikova YV, Muslimov AR, et al. Overcoming the delivery problem for therapeutic genome editing: Current status and perspective of non-viral methods. Biomaterials 2020; 258: 120282.
[http://dx.doi.org/10.1016/j.biomaterials.2020.120282] [PMID: 32798742]
[52]
Kim JA, Cho K, Shin MS, et al. A novel electroporation method using a capillary and wire-type electrode. Biosens Bioelectron 2008; 23(9): 1353-60.
[http://dx.doi.org/10.1016/j.bios.2007.12.009] [PMID: 18242073]
[53]
Binder S, Stolba U, Krebs I, et al. Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: A pilot study. Am J Ophthalmol 2002; 133(2): 215-25.
[http://dx.doi.org/10.1016/S0002-9394(01)01373-3] [PMID: 11812425]
[54]
Binder S, Krebs I, Hilgers RD, et al. Outcome of transplantation of autologous retinal pigment epithelium in age-related macular degeneration: A prospective trial. Invest Ophthalmol Vis Sci 2004; 45(11): 4151-60.
[http://dx.doi.org/10.1167/iovs.04-0118] [PMID: 15505069]
[55]
Binder S. The macula. Diagnosis, treatment and future trends. New York: Springer-VerlaglWien 2004.
[http://dx.doi.org/10.1007/978-3-7091-7985-7]
[56]
da Cruz L, Fynes K, Georgiadis O, et al. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol 2018; 36(4): 328-37.
[http://dx.doi.org/10.1038/nbt.4114] [PMID: 29553577]
[57]
Stanga PE, Kychenthal A, Fitzke FW, et al. Retinal pigment epithelium translocation after choroidal neovascular membrane removal in age-related macular degeneration. Ophthalmology 2002; 109(8): 1492-8.
[http://dx.doi.org/10.1016/S0161-6420(02)01099-0] [PMID: 12153801]
[58]
van Zeeburg EJT, Maaijwee KJM, Missotten TOAR, Heimann H, van Meurs JC. A free retinal pigment epithelium-choroid graft in patients with exudative age-related macular degeneration: Results up to 7 years. Am J Ophthalmol 2012; 153(1): 120-7.
[http://dx.doi.org/10.1016/j.ajo.2011.06.007] [PMID: 21907969]
[59]
Chen FK, Uppal GS, MacLaren RE, et al. Long-term visual and microperimetry outcomes following autologous retinal pigment epithelium choroid graft for neovascular age-related macular degeneration. Clin Exp Ophthalmol 2009; 37(3): 275-85.
[http://dx.doi.org/10.1111/j.1442-9071.2009.01915.x] [PMID: 19459869]
[60]
Mandai M, Watanabe A, Kurimoto Y, et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 2017; 376(11): 1038-46.
[http://dx.doi.org/10.1056/NEJMoa1608368] [PMID: 28296613]
[61]
Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000; 45(2): 115-34.
[http://dx.doi.org/10.1016/S0039-6257(00)00140-5] [PMID: 11033038]
[62]
Ung L, Pattamatta U, Carnt N, Wilkinson-Berka JL, Liew G, White AJR. Oxidative stress and reactive oxygen species: A review of their role in ocular disease. Clin Sci (Lond) 2017; 131(24): 2865-83.
[http://dx.doi.org/10.1042/CS20171246] [PMID: 29203723]
[63]
Cao W, Tombran-Tink J, Chen W, Mrazek D, Elias R, McGinnis JF. Pigment epithelium-derived factor protects cultured retinal neurons against hydrogen peroxide-induced cell death. J Neurosci Res 1999; 57(6): 789-800.
[http://dx.doi.org/10.1002/(SICI)1097-4547(19990915)57:6<789::AID-JNR4>3.0.CO;2-M] [PMID: 10467250]
[64]
Pang IH, Zeng H, Fleenor DL, Clark AF. Pigment epithelium-derived factor protects retinal ganglion cells. BMC Neurosci 2007; 8: 11.
[http://dx.doi.org/10.1186/1471-2202-8-11] [PMID: 17261189]
[65]
Wang X, Liu X, Ren Y, et al. PEDF protects human retinal pigment epithelial cells against oxidative stress via upregulation of UCP2 expression. Mol Med Rep 2019; 19(1): 59-74.
[PMID: 30431098]
[66]
Brook N, Brook E, Dharmarajan A, Chan A, Dass CR. The role of pigment epithelium-derived factor in protecting against cellular stress. Free Radic Res 2019; 53(11-12): 1166-80.
[http://dx.doi.org/10.1080/10715762.2019.1697809] [PMID: 31760841]
[67]
Choi JK, Choi BH, Ha Y, et al. Signal transduction pathways of GM-CSF in neural cell lines. Neurosci Lett 2007; 420(3): 217-22.
[http://dx.doi.org/10.1016/j.neulet.2007.03.065] [PMID: 17556097]
[68]
Chao J-R, Wang J-M, Lee S-F, et al. mcl-1 is an immediate-early gene activated by the granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling pathway and is one component of the GM-CSF viability response. Mol Cell Biol 1998; 18(8): 4883-98.
[http://dx.doi.org/10.1128/MCB.18.8.4883] [PMID: 9671497]
[69]
Geiger RC, Waters CM, Kamp DW, Glucksberg MR. KGF prevents oxygen-mediated damage in ARPE-19 cells. Invest Ophthalmol Vis Sci 2005; 46(9): 3435-42.
[http://dx.doi.org/10.1167/iovs.04-1487] [PMID: 16123449]
[70]
Zhuge CC, Xu JY, Zhang J, et al. Fullerenol protects retinal pigment epithelial cells from oxidative stress-induced premature senescence via activating SIRT1. Invest Ophthalmol Vis Sci 2014; 55(7): 4628-38.
[http://dx.doi.org/10.1167/iovs.13-13732] [PMID: 24845634]
[71]
Tu G, Zhang YF, Wei W, et al. Allicin attenuates H2O2-induced cytotoxicity in retinal pigmented epithelial cells by regulating the levels of reactive oxygen species. Mol Med Rep 2016; 13(3): 2320-6.
[http://dx.doi.org/10.3892/mmr.2016.4797] [PMID: 26781848]
[72]
Hao Yiming, Liu Jie, Ziyuan Wang LY. Piceatannol protects human retinal pigment epithelial cells against hydrogen peroxide induced oxidative stress and apoptosis through modulating P13K/Akt signaling pathway. Nutrients 2019; 11: 1-13.
[http://dx.doi.org/10.3390/nu11071515]
[73]
Pérez-León J, Frech MJ, Schröder JE, et al. Spontaneous synaptic activity in an organotypic culture of the mouse retina. Invest Ophthalmol Vis Sci 2003; 44(3): 1376-87.
[http://dx.doi.org/10.1167/iovs.02-0702] [PMID: 12601071]
[74]
Krasnov MS, Grigorian EN, Iamskova VP. An organotypic culture of the newt retina together with other tissues of the posterior eye segment as a model for studying the effects of the cell adhesion glycoproteins. Izv Akad Nauk Ser Biol 2003; 30(1): 22-36.
[PMID: 12647537]
[75]
Li Y, Zhang Y, Qi S, Su G. Retinal organotypic culture - a candidate for research on retinas. Tissue Cell 2018; 51: 1-7.
[http://dx.doi.org/10.1016/j.tice.2018.01.005] [PMID: 29622082]
[76]
Hernández-Pinto A, Polato F, Subramanian P, et al. PEDF peptides promote photoreceptor survival in rd10 retina models. Exp Eye Res 2019; 184: 24-9.
[http://dx.doi.org/10.1016/j.exer.2019.04.008] [PMID: 30980815]
[77]
Chen Y, Yang J, Geng H, et al. Photoreceptor degeneration in microphthalmia (Mitf) mice: Partial rescue by pigment epithelium-derived factor. Dis Model Mech 2019; 12(1): 1-9.
[http://dx.doi.org/10.1242/dmm.035642] [PMID: 30651300]
[78]
Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 2013; 12(12): 931-47.
[http://dx.doi.org/10.1038/nrd4002] [PMID: 24287781]
[79]
Donadelli M, Dando I, Fiorini C, Palmieri M. UCP2, a mitochondrial protein regulated at multiple levels. Cell Mol Life Sci 2014; 71(7): 1171-90.
[http://dx.doi.org/10.1007/s00018-013-1407-0] [PMID: 23807210]
[80]
Kropp M, Tobalem S, Kecik M, et al. Improved transferability of a disease model for avascular age-related macular degeneration (AMD) to evaluate cell-based gene therapies using aged mice. ISSCR Annual meeting. Boston, USA. 2020. Meeting Abstract: MDD228. Poster

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