J.ophthalmol.(Ukraine).2021;1:70-75.
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http://doi.org/10.31288/oftalmolzh202117075 Received: 10 July 2020; Published on-line: 12 February 2021 Results and possible prospects of genetic technology in ophthalmology (literature review). Part I N. A. Gavrilova, O. Ie. Tishchenko, A. V. Zinov’eva A.I. Yevdokimov Moscow State University of Medicine and Dentistry; Moscow (Russian Federation) E-mail: aleksandra.r@live.ru TO CITE THIS ARTICLE: Gavrilova NA, Tishchenko OIe, Zinov’eva AV. Results and possible prospects of genetic technology in ophthalmology (literature review). Part I. J.ophthalmol.(Ukraine).2021;1:70-75. http://doi.org/10.31288/oftalmolzh202117075 The emergence of fundamentally novel technological solutions in the field of gene therapy today, the formation of the priority and the development of genetic technologies create serious prerequisites for the beginning of a new Fusion era in ophthalmology in the near future. This review, in its first part, presents the results of fundamental and clinical studies on the use of viral and non-viral systems for the delivery of genetic material in ophthalmology. The second part of the review will focus on genetic therapeutic strategies (gene replacement, gene suppression, genomic editing using CRISPR / Cas9 technology, priming and transposon editing) that have been used in ophthalmology over the past several years. Keywords: viral vectors, gene therapy, retina
The basic Principles of the Predictive, Preventive and Personalized Medicine as the Healthcare Model of the near future, as well as the Strategy for the Development of Medical Science in Russia for the Period until 2025, require that researches in healthcare (particularly, but not only, eye care) shall focus on the areas associated with the genetic, cellular, nano- and information technologies [1]. The emergence of fundamentally novel technological solutions in the field of gene therapy and gene diagnostics, the creation of priority for and development of genetic technologies create serious prerequisites for the beginning of a new Fusion era in ophthalmology in the near future. Before we overview current genetic technologies in ophthalmology and make the analysis of global trends in these technologies, we consider current normative legal support and maintenance in the area of developing genetic technologies. The Federal Research Program for Genetic Technologies Development until 2027 was approved in 2019 [2]. A Program’s key objective is to implement a comprehensive solution to the task of the accelerated development of genetic technologies, including genetic editing. The meeting of the Working Group on Legal Regulation in the Area of Genetic Technologies, Including Genetic Editing and Bioethics on October 16, 2020, adopted a decision on the establishment of the Center for Law and Bioethics Related to Genomic Research and Technologies, the principal aim of which is to provide legal support for the accelerated development and application of genetic technologies. The Center for Precision Genetic Editing and Genetic Technologies in Biomedicine has been established within the framework of the program and the national project named “Science”. Gene therapy. Gene delivery systems The gene delivery systems can be divided into two classes, viral and non-viral; either has its advantages and disadvantages. Viral gene delivery systems Recombinant-deficient viral vectors (viruses that are no longer able to replicate) are commonly used for the delivery of genetic material into cells. The types of vectors available for the delivery include adenoviruses, adeno-associated viruses, lentiviruses and herpes simplex viruses. Adenoviruses have a rather high capacity for gene transfer (their vectors can carry long fragments of DNA, more than 20,000 base pairs, or 20 kb), a high level of transduction (DNA transfer to target cells), and their viral DNA does not integrate into the host cell DNA (the genetic material remains in the cytoplasm and is not delivered into the nucleus, which is both an advantage and a disadvantage, because transgene expression is transient); in addition, they are highly immunogenic (not safe) [3, 4]. Recombinant adeno-associated viruses (AAV) are attractive vectors for several reasons: they are non-pathogenic, have a low immunogenicity, display broad tropism to most cells and tissues, high transduction efficacy, integrate into the host DNA at the particular site, and can trigger long-term transgene expression. One limitation of recombinant AAV is that their genome-packaging capacity is not ≤ ~ 5 kb. Experimental studies on the use of AAV for induced neovascularization models of retinal and optic nerve disorders (age-related macular degeneration (AMD), pigmented retinitis, Leber’s amaurosis and Stargardt disease) have been widely conducted in recent years [5-19]. Retinal, corneal, and trabecular meshwork transductions have been found to be effective for the various AAV variants and various routes of AAV delivery. Boye and colleagues [20] used a mixture of viscoelastic (Healon) and AAV to place sub-inner limiting membrane (ILM) injections in the primate retina, and demonstrated uniform and extensive transduction of retinal ganglion cells (RGCs) in the areas beneath the subILM bleb. Simpson and colleagues [21] suggested that AAV-PHP.eB, a novel AAV9-based mutant capsid, crosses the intra-retinal blood-retinal barrier (IR-BRB), efficiently transduces horizontal cells located adjacent to IR-BRB, but has very limited ability to further penetrate retina and reach photoreceptors. Lee and colleagues [22] evaluated the transduction efficiencies of four different AAV serotypes, AAV2, 5, 8, and 9, in streptozotocin (STZ)-induced diabetic mouse retinas. AAV2 and AAV9 displayed the most efficient transduction. Particularly, AAV2 was transduced into various retinal cells, including Müller cells, microglia, retinal ganglion cells (RGCs), bipolar cells, horizontal cells, and amacrine cells, whereas AAV9 was effectively transduced only into RGC and horizontal cells [22]. In a mouse study by Wang and colleagues [23], a synthetically developed AAV transduced following a single intracameral injection efficiently the trabecular meshwork, corneal stroma, and endothelial cells. In a mouse study by Lee and colleagues [24], laser photocoagulation induced transduction of retinal cells by intravitreally administered AAV. Lentiviruses (LV) belong to the family of retroviruses, have a rather small genome-packaging capacity (≤8 kb), can trigger long-term transgene expression, and induce minimal host immune response. However, they randomly integrate into the genome and can cause insertional mutagenesis by disrupting other genes, leading to severe adverse events. In ophthalmological studies, lentiviruses have been less frequently used for genetic material delivery than AAV. They have been used for vitreoretinal disorders, AMD, diabetic retinopathy, choroidal melanoma, retinoblastoma, neovascularization, and corneal dystrophy [11, 25-29]. In an interesting rat study by Bai and colleagues [30], LV mediated toll-like receptor 2 (TLR2) small interference RNA (SiRNA) could effectively down regulate the TLR2 expression via RNA interference and prolong the survival of corneal grafts, although not necessarily able to prevent the rejection. Therefore, currently, fundamental studies on the use of AAV and LV for the delivery of genetic material into the eye are widely conducted. Particularly, they found that: (1) retinal, corneal, and trabecular meshwork transductions are effective for the various AAV variants and various routes of AAV delivery; (2) different AAV serotypes differ in transduced cells and tissues of the eye; (3) the efficacy of genetic therapy mostly depends on the route of delivery. As at August, 2019, according to online Wiley library records (http://www.abedia.com/wiley/indications.php), the total number of clinical studies on gene therapy drugs was 3000. Of these, 95% were phase 1/2 studies, and 5% were phase 2/3 studies. In addition, as at August, 2019, postmarketing studies were being conducted only for 5 gene therapy drugs. Only 9 gene therapy drugs have been approved for use by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA). Luxturna (Spark Therapeutics, Philadelphia, PA), an AAV-based vector carrying a normal copy of the RPE65 gene to the RPE cells that are lacking a normally functioning RPE65 gene, was approved for the treatment of biallelic RPE65mutation–associated retinal dystrophy (Leber congenital amaurosis) by the FDA in 2017, and by the Committee for Medicinal Products for Human Use (CHMP) of the EMA in 2018. Luxturna is injected subretinally once per eye, for patients who have confirmed RPE65 mutations and enough viable cells in their retina [31, 32]. The first commercial gene therapy with Luxturna was performed at the Children's Hospital Los Angeles in 2018. Efficacy and safety studies of AAV-mediated delivery of the genetic material to the eye have been widely conducted in recent years. GenVec (Gaithersburg, MD) assessed the safety of a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium-derived factor (AdPEDF.11) for advanced neovascular AMD in a phase I clinical trial [33]. There were no serious adverse events related to AdPEDF.11, but signs of mild, transient intraocular inflammation occurred in 25% of patients. Avalanche Biotechnologies (Menlo Park, CA) in collaboration with the Australian Lions Eye Institute investigated the safety profile and effectiveness of subretinal injections of rAAV sFLT-1 recombinant AAV (rAAV) soluble fms-like tyrosine kinase-1 (sFLT-1) for neovascular AMD in Phase 1 and 2a human clinical trials [34, 35]. A subretinal injection of a low-dose (1×1010 vector genomes (vg)) or high-dose (1×1011 vg) sFLT-1 was found to be safe, and administration of anti-VEGF gene therapy for neovascular AMD was found to be promising. CD59 complement factor is a membrane-bound inhibitor of the membrane attack complex (MAC), an immune protein that mediates cell lysis by the formation of plasma membrane pores. Hemera Biosciences (Waltham, MA) carried out a phase I gene therapy trial to evaluate the safety of MAC inhibition via intravitreal delivery of an adeno-associated virus vector (AAV2) that expresses the soluble form of membrane-independent CD59 (sCD59), AAVCAGsCD59 (HMR59), in participants with dry AMD [36]. The trial found HMR-59 to be safe and effective, and, of the patients with at least 6 months of therapy, 18% did not require anti-VEGF treatment within this period [37]. Oxford BioMedica (UK) Ltd carried out a phase I trial in patients with advanced NVAMD, the Gene Transfer of Endostatin/angiostatin for Macular Degeneration Trial (GEM Study), to test the safety and bioactivity of subretinal injection of a lentiviral Equine Infectious Anemia Virus (EIAV) vector expressing the angiogenesis inhibitors endostatin and angiostatin (RetinoStat®) [27]. The study findings demonstrated that lentiviral EIAV vectors provide a safe platform with robust and sustained transgene expression for ocular gene therapy. Adverum Biotechnologies (Menlo Park, CA) started a phase I trial to study the safety profile of intravitreal ADVM-022, a novel recombinant AAV, in 2018. ADVM-022 utilizes the AAV2.7m8 capsid, which carries a strong, ubiquitous expression cassette encoding a codon-optimized cDNA of the aflibercept protein. Patients with AMD and active CNV had an intravitreal injection of 6E11 vg/eye or 2 6E11 vg/eye as per the study protocol. The study is still ongoing and the final results have not been presented as yet. A phase 1/2 study evaluated the safety and tolerability of RGX-314 (RegenexBio) in patients with wet AMD. RGX-314 is an AAV8 vector encoding for a soluble anti-VEGF Fab protein, which binds to RPE cells to produce a therapeutic anti-VEGF protein. The gene encodes for an anti-VEGF fragment of a monoclonal antibody. The safety of different doses of RGX-314 (3E9 GC, 1E10 GC, 6E10 GC, 1.6E11 GC, and 2.5E11 GC) was evaluated in a phase 1 trial. Stabilization of the process was observed in 73% of the cases within 6 months, and in 50% of the cases within 18 months, and patients did not require anti-VEGF treatment within these periods. A long-term follow-up study of RGX-314 (RGX-314 LTFU) was initiated in December, 2019. Non-viral gene delivery systems These include plasmid DNA that is either delivered directly (termed “naked DNA”) or complexed with carriers (e.g., metal-based, polymer-based or lipid-based nanoparticles). Non-viral gene delivery systems may offer a less invasive, low immunogenic and inflammatory response than viral systems and can package rather large plasmids. What is more, and important to consider, they are more attractive for manufacturers because their manufacturing cost is lower and they are more easily standardized. The major disadvantage is low efficiency of transfection of the genetic material into a cell. Naked DNA is the simplest gene delivery system. In this case, they use a gene which is joined by a relatively low number of nucleotide sequences. Although there have been relatively few reports on studies with naked DNA, they found the reporter plasmid DNA to be efficiently transduced and transfected into retinal cells [38, 39]. Metal-based, polymer-based and lipid-based nanoparticles are more common and successful gene delivery systems compared to naked DNA. Metal-based (cerium oxide and yttrium oxide) nanoparticles are non-toxic for ocular tissues and provide antioxidant protection in retinal disorders [40-44]. Polymer-based nanoparticles have recently attracted the attention of researchers because they can be rather easily manufactured and have controllable characteristics. Particular attention is paid to the CK30-PEG compacted DNA nanoparticles that have been successfully tested in the eye. These particles have been demonstrated to be non-immunogenic in various tissues. In addition, in several studies, they have been used for gene transfer in models of retinitis pigmentosa and diabetic retinopathy, and were supposed to be promising for these disorders [45, 46]. Lipid-based delivery systems (liposomes, DNA-lipid complexes, and etc.) are currently one of the most commonly used types of nanoparticle carriers. Gao and colleagues [47] constructed the orongoxygen induced retinopathy (OIR) mouse (C57BL/6J) model and evaluated targeting VEGF siRNA transfection by new polymeric liposomes to inhibit retinal neovascularization. They found this approach to produce a durable therapeutic effect, with a significantly reduced area of retinal neovascularization [47]. A disadvantage of lipid-based delivery systems is the lack of cell specificity which may result in non-target effects. Wang and colleagues [48] demonstrated that cell-specific promoters enable lipid-based nanoparticles to deliver genes to specific cells of the retina in vivo. A novel method of targeted delivery of the genetic material has been recently developed, which enables transfection of rather large gene constructs. The technique utilizes polymer-covered gold nanorods and near-infrared laser irradiation, with gold nanoparticles having a maximum absorption spectrum in this region. These nanorods are heated with application of a laser pulse, and, when nanoparticles are in contact with the cell membrane, the nanorods enable site-specific transfection of large gene constructs due to increased permeability of the cell membrane without non-target effects [49].
Conclusion Therefore, the results of ophthalmological clinical studies demonstrate that applications of gene therapy drugs delivered by viral (mainly, AAV) and non-viral systems are safe and effective, and that gene therapy seems promising for the treatment of various eye disorders. We, however, need to bear in mind that (a) AAV can show immunogenicity (especially, associated with repeat injections), (b) LLV can cause insertional mutagenesis and carcinogenesis, and (c) liposome-based delivery systems do not always allow for cell-specific transport mechanisms, which can produce non-target effects. Today, the major objectives in the area of systems for gene therapy delivery to the eye are targeted delivery of the genetic material and transduction/transfection of large therapeutic genes.
References 1.Order of the Ministry of Health of Russia dated March 30, 2013 No. 175 "On approval of the action plan for the implementation of the Strategy for the development of medical science in the Russian Federation for the period up to 2025, approved by the order of the Government of the Russian Federation No. 2580-r dated December 28, 2012" (as amended by dated June 26, 2015 No. 373). Collection of legislation of the Russian Federation. 2013;2:111. Russian. 2.Resolution of the Government of the Russian Federation dated April 22, 2019 No. 479 "On approval of the Federal Scientific and Technical Program for the Development of Genetic Technologies for 2019 - 2027". Collection of legislation of the Russian Federation. 2019;7:2108. Russian. 3.Rotov AYu, Nikolaeva DA., Astakhova LA., Firsov M.L. [Viral vectors for optogenetic retinal prosthetics]. Russian physiological journal I.M.Sechenova. 2018; 104 (12): 1391-408. Russian. 4.Supotnitskiy MV. [Genotherapeutic vector systems based on viruses]. Biopreparats (Biopharmaceuticals). 2011;3:15-26. Russian. 5.Alves C.H., Wijnholds J. AAV Gene Augmentation Therapy for CRB1-Associated Retinitis Pigmentosa. Methods Mol Biol. 2018;1715:135‐151. 6.Bosco A, Anderson SR, Breen KT, Romero CO, Steele MR, Chiodo VA, Boye SL, Hauswirth WW, Tomlinson S, Vetter ML. Complement C3-Targeted Gene Therapy Restricts Onset and Progression of Neurodegeneration in Chronic Mouse Glaucoma. Mol Ther. 2018;26(10):2379‐2396. 7.Chekuri A, Sahu B, Chavali VRM, Voronchikhina M, Soto-Hermida A, Suk JJ, Alapati AN, Bartsch D-U, Ayala-Ramirez R, Zenteno JC, Dinculescu A, Jablonski MM, Borooah S, Ayyagari R. Human Gene Therapy. 2019;632-650. 8.Dyka FM, Molday LL, Chiodo VA, Molday RS, Hauswirth WW. Dual ABCA4-AAV Vector Treatment Reduces Pathogenic Retinal A2E Accumulation in a Mouse Model of Autosomal Recessive Stargardt Disease. Hum Gene Ther. 2019;30(11):1361‐70. 9.Feathers KL, Jia L, Perera ND, Chen A, Presswalla FK, Khan NW, Fahim AT, Smith AJ, Ali RR, Thompson DA. Development of a Gene Therapy Vector for RDH12-Associated Retinal Dystrophy. Hum Gene Ther. 2019;30(11):1325‐35. 10.Gamlin PD, Alexander JJ, Boye SL, Witherspoon CD, Boye SE. SubILM Injection of AAV for Gene Delivery to the Retina. Methods Mol Biol. 2019;1950:249‐62. 11.Kalesnykas G, Kokki E, Alasaarela L, Lesch HP, Tuulos T, Kinnunen K, Uusitalo H, Airenne K, Yla-Herttuala S. Comparative Study of Adeno-associated Virus, Adenovirus, Bacu lovirus and Lentivirus Vectors for Gene Therapy of the Eyes. Curr Gene Ther. 2017;17(3):235‐247. 12.Lipinski D.M. A Comparison of Inducible Gene Expression Platforms: Implications for Recombinant Adeno-Associated Virus (rAAV) Vector-Mediated Ocular Gene Therapy. Adv Exp Med Biol. 2019;1185:79-83. 13.Moore NA, Bracha P, Hussain RM, Morral N, Ciulla TM. Gene therapy for age-related macular degeneration. Expert Opinion on Biological Therapy. 2017;10:1235-1244. 14.Patrício MI, Barnard AR, Xue K, MacLaren RE. Choroideremia: molecular mechanisms and development of AAV gene therapy. Expert Opin Biol Ther. 2018;18(7):807‐820. 15.Ramachandran PS, Lee V, Wei Z, Song JY, Casal G, Cronin T, et al. Evaluation of Dose and Safety of AAV7m8 and AAV8BP2 in the Non-Human Primate Retina. Hum Gene Ther. 2017;28(2):154‐67. 16.Simpson EM, Korecki AJ, Fornes O, McGill TJ, Cueva-Vargas JL, Agostinone J, et al. New MiniPromoter Ple345 (NEFL) Drives Strong and Specific Expression in Retinal Ganglion Cells of Mouse and Primate Retina. Hum Gene Ther. 2019;30(3):257‐72. 17.Sun P, Liu Z. Overexpressing kringle 1 domain of hepatocyte growth factor with adeno-associated virus inhibits the pathological retinal neovascularization in an oxygen-induced retinopathy mouse model. Biochem Biophys Res Commun. 2019;508(1):130‐137. 18.Wang SK, Xue Y, Rana P, Hong CM., Cepko CL. Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa. Proc Natl Acad Sci USA. 2019;116(20):10140‐10149. 19.Xue K, MacLaren RE. Ocular gene therapy for choroideremia: clinical trials and future perspectives. Expert Rev Ophthalmol. 2018;13(3):129‐138. 20.Boye SE, Alexander JJ, Witherspoon CD, Boye SL, Peterson JJ, Clark ME, Sandefer KJ, Girkin CA, Hauswirth WW, Gamlin PD. Highly efficient delivery of adeno-associated viral vectors to the primate retina. Hum Gene Ther. 2016;27:580597. 21.Simpson CP, Bolch SN, Zhu P, Weidert F, Dinculescu A, Lobanova ES. Systemic Delivery of Genes to Retina Using Adeno-Associated Viruses. Adv Exp Med Biol. 2019;1185:109‐12. 22.Lee SH, Yang JY, Madrakhimov S, Park HY, Park K, Park TK. Adeno-Associated Viral Vector 2 and 9 Transduction Is Enhanced in Streptozotocin-Induced Diabetic Mouse Retina. Mol Ther Methods Clin Dev. 2018;13:55-66. 23.Wang L, Xiao R, Andres-Mateos E, Vandenberghe LH. Single stranded adeno-associated virus achieves efficient gene transfer to anterior segment in the mouse eye. PLoS One. 2017;12(8):e0182473. 24.Lee SH, Kong YJ, Lyu J, Lee H. Park K, Park TK. Laser Photocoagulation Induces Transduction of Retinal Pigment Epithelial Cells by Intravitreally Administered Adeno-Associated Viral Vectors. Hum Gene Ther Methods. 2015;26(5):159‐61. 25.Aktas Z, Rao H, Slauson SR, Gabelt BA, Larsen IV, Sheridan RTC, Herrnberger L, Tamm ER, Kaufman PL, Brandt CR. Proteasome Inhibition Increases the Efficiency of Lentiviral Vector-Mediated Transduction of Trabecular Meshwork. Invest Ophthalmol Vis Sci. 2018;59(1):298‐310. 26.Basche M, Kampik D, Kawasaki S, Branch MJ, Robinson M, Larkin DF, Smith AJ, Ali RR. Sustained and Widespread Gene Delivery to the Corneal Epithelium via In Situ Transduction of Limbal Epithelial Stem Cells, Using Lentiviral and Adeno-Associated Viral Vectors. Hum Gene Ther. 2018;29(10):1140‐1152. 27.Campochiaro PA, Lauer AK, Sohn EH, Mir TA, Naylor S, Anderton MC, Kelleher M, Harrop R, Ellis S, Mitrophanous KA. Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study. Hum Gene Ther. 2017;28(1):99-111. 28.Liu S, Song W, Liu F, Zhang J, Zhu S. Antitumor efficacy of VP22-CD/5-FC suicide gene system mediated by lentivirus in a murine uveal melanoma model. Exp Eye Res. 2018;172:144-51. 29.Wert KJ, Mahajan VB. In Vivo Expression of Mutant Calpains in the Eye Using Lentivirus. Methods Mol Biol. 2019;1915:233-247. 30.Bai L., Liang W., Chen M., Cissé Y., Liu J., Su Y., Yu J., Liu Q. Effect of Lentivirus-Mediated Gene Silencing, Targeting Toll-Like Receptor 2, on Corneal Allograft Transplantation in Rats. Mol Immunol. 2017;91:97-104. 31.Russell S, Bennett J, Wellman JA, Chung DC , Yu Z-F, Tillman A, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849‐60. 32.Maguire AM, Russell S, Wellman JA, Chung DC, Yu ZF, Tillman A, et al. Efficacy, safety, and durability of voretigeneneparvovec-rzyl in RPE65 mutation-associated inherited retinal dystrophy: results of phase 1 and 3 trials. Ophthalmology. 2019;26:1273–1285 33.Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, et al. Adenoviral vectordelivered pigment epithelium-derived factor for neovascular agerelated macular degeneration: results of a phase I clinical trial. Hum Gene Ther. 2006;17(2):167–76. 34.Constable IJ, Lai CM, Magno AL, French MA, Barone SB, Schwartz SD, Blumenkranz MS, Degli-Esposti MA, Rakoczy EP. Gene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation Trial. Am J Ophthalmol. 2017;177:150-158. 35.Rakoczy EP, Magno AL, Lai CM, Pierce CM, Degli-Esposti MA, Blumenkranz MS, Constable IJ. Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. Am J Ophthalmol. 2019;204:113-123. 36.Cashman SM, Ramo K, Kumar-Singh R. A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration. PLoS One. 2011;6(4):e19078. 37.Dugel P.U. Clinical trial download: Data on a Gene Therapy for Dry and Wet AMD. A phase 1 clinical trial program is targeting both disease states. Retinal Physician. 2020;17:16-7. 38.Dezawa M, Takano M, Negishi H, Mo X, Oshitari T, Sawada H. Gene transfer into retinal ganglion cells by in vivo electroporation: a new approach. Micron. 2002;33(1):1‐6. 39.Matsuda T, Cepko CL. Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc Natl Acad Sci USA. 2004;101(1):16‐22. 40.Cai X, Yodoi J, Seal S, et al. Nanoceria and thioredoxin regulate a common antioxidative gene network in tubby mice. Adv Exp Med Biol. 2014;801:829–836. 41.Cai X, McGinnis JF. Nanoceria: a Potential Therapeutic for Dry AMD. Adv Exp Med Biol. 2016;854:111–118. 42.Cai X, Seal S, McGinnis JF. Sustained inhibition of neovascularization in vldlr−/− mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-kappaB pathway. Biomaterials. 2014;35:249–258. 43.Nita M, Grzybowski A. The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults. Oxid Med Cell Longev. 2016:3164734. 44.Wong LL, McGinnis JF. Nanoceria as bona fide catalytic antioxidants in medicine: what we know and what we want to know. Adv Exp Med Biol. 2014;801:821–8. 45.Han Z, Banworth MJ, Makkia R, Conley SM, Al-Ubaidi MR, Cooper M.J., Naash MI. Genomic DNA nanoparticles rescue rhodopsin-associated retinitis pigmentosa phenotype. FASEB J. 2015;29:2535–2544. 46.Mitra RN, Nichols CA, Guo J, Makkia R, Cooper MJ, Naash MI, Hana Z. Nanoparticle-mediated miR200-b delivery for the treatment of diabetic retinopathy. J Control Release. 2016;236:31–37. 47.Gao Y, Liu X, Li C, Peng Y, Yang J, Wang X, Li X. Targeting VEGF siRNA Transfection by New Polymeric Liposomes to Inhibit Retinal Neovascularization. Zhonghua Yan Ke Za Zhi. 2015;51(5):344‐350. 48.Wang Y, Rajala A, Cao B, Ranjo-Bishop M, Agbaga M-P, Mao C, Rajala R.V.S. Cell-Specific Promoters Enable Lipid-Based Nanoparticles to Deliver Genes to Specific Cells of the Retina In Vivo. Theranostics. 2016;6:1514–27. 49.Batabyal S, Gajjeraman S, Tchedre K, Dibas A, Wright W, Mohanty S. Near-Infrared Laser-Based Spatially Targeted Nano-enhanced Optical Delivery of Therapeutic Genes to Degenerated Retina. Mol Ther Methods Clin Dev. 2020;17:758–70.
The authors declare no conflict of interest which could influence their opinions on the subject or the materials presented in the manuscript
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