Importance of Nonhuman Primates as a Model System for Gene Therapy Development in Ophthalmology

Abstract

Gene therapy is a treatment concept that uses, in most cases, viral vectors to deliver a therapeutic transgene to target cells. Although the idea of gene therapy dates back over 50 years ago, due to the complexity of the treatment concept, it took until the last decade for the responsible agencies like FDA and EMA to recommend the first gene therapy products for clinical use. The development of these therapies relies on molecular engineering of specifically designed vectors and models to test the effectiveness and safety of the treatment. Despite an increasing effort to find effective surrogates, animal models are still irreplaceable in gene therapy development. Rodents are important for exploring pathways and disease mechanisms and identifying potential treatment targets. However, only the primate eye resembles the human eye to a degree where most structures are nearly identical. Some research questions can therefore only be answered using a nonhuman primate (NHP) model. In this review, we want to summarize these key features and highlight the importance of the NHP model for gene therapy development in ophthalmology.

Zusammenfassung

Bei der Gentherapie wird mittels eines meist viralen Vektors ein spezifisch entwickeltes therapeutisches Transgen in bestimmte Zielzellen eingeschleust. Zur Erreichung dieses Ziels waren viele Jahrzehnte an Forschung notwendig und erst seit ungefähr 10 Jahren gibt es die ersten am Menschen zugelassenen Gentherapien. Unverzichtbar für die Entwicklung sind die Methoden der modernen Molekulargenetik und -technik sowie geeignete Tiermodelle. Die zunehmend besseren Alternativen können die gängigen Tiermodelle zum jetzigen Zeitpunkt allerdings noch nicht vollständig ersetzen. Mausmodelle nehmen weiterhin aufgrund ihrer vielen Vorteile eine tragende Rolle ein. Jedoch bestehen grundlegende Unterschiede zur Physiologie und Anatomie insbesondere der Netzhaut des Menschen, weshalb sie für diesbezügliche Fragestellungen nur bedingt geeignet sind. Die Augen der Primaten sind hingegen denen des Menschen in strukturellem Aufbau der Netzhaut und des Auges sehr ähnlich. Dadurch besteht eine deutlich bessere Vergleichbarkeit für bestimmte Fragestellungen in der Entwicklung von Gentherapien am Auge. In diesem Artikel möchten wir die Relevanz von Tiermodellen an sog. nicht menschlichen Primaten in der Entwicklung von Gentherapien am Auge darstellen.

Key words

gene therapy - drug development - animal models

Schlüsselwörter

Gentherapie - Therapieentwicklung - Tiermodell

Publikationsverlauf

Eingereicht: 06. Oktober 2021

Angenommen: 16. Februar 2022

Accepted Manuscript online:
21. Februar 2022

Artikel online veröffentlicht:
22. März 2022

• References

• 1 Fischer MD, Ochakovski GA, Beier B. et al. Changes in retinal sensitivity after gene therapy in choroideremia. Retina 2020; 40: 160-168 DOI: 10.1097/iae.0000000000002360.
• 2 Fischer MD, Michalakis S, Wilhelm B. et al. Safety and Vision Outcomes of Subretinal Gene Therapy Targeting Cone Photoreceptors in Achromatopsia: A Nonrandomized Controlled Trial. JAMA Ophthalmol 2020; 138: 643-651 DOI: 10.1001/jamaophthalmol.2020.1032.
• 3 Ye GJ, Budzynski E, Sonnentag P. et al. Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-CB-hRS1, a Recombinant Adeno-Associated Virus Vector Expressing Retinoschisin. Hum Gene Ther Clin Dev 2015; 26: 165-176 DOI: 10.1089/humc.2015.076.
• 4 Grishanin R, Vuillemenot B, Sharma P. et al. Preclinical Evaluation of ADVM-022, a Novel Gene Therapy Approach to Treating Wet Age-Related Macular Degeneration. Mol Ther 2019; 27: 118-129 DOI: 10.1016/j.ymthe.2018.11.003.
• 5 Maclachlan TK, Lukason M, Collins M. et al. Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration. Mol Ther 2011; 19: 326-334 DOI: 10.1038/mt.2010.258.
• 6 Seitz IP, Michalakis S, Wilhelm B. et al. Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates. Invest Ophthalmol Vis Sci 2017; 58: 5792-5801 DOI: 10.1167/iovs.17-22473.
• 7 Winkler PA, Occelli LM, Petersen-Jones SM. Large Animal Models of Inherited Retinal Degenerations: A Review. Cells 2020; 9: 882 DOI: 10.3390/cells9040882.
• 8 Fauser S, Luberichs J, Schüttauf F. Genetic Animal Models for Retinal Degeneration. Surv Ophthalmol 2002; 47: 357-367 DOI: 10.1016/S0039-6257(02)00314-4.
• 9 Sahly I, Dufour E, Schietroma C. et al. Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice. J Cell Biol 2012; 199: 381-399 DOI: 10.1083/jcb.201202012.
• 10 Shah M, Cabrera-Ghayouri S, Christie LA. et al. Translational Preclinical Pharmacologic Disease Models for Ophthalmic Drug Development. Pharm Res 2019; 36: 58 DOI: 10.1007/s11095-019-2588-5.
• 11 Koster C, Wever KE, Wagstaff PE. et al. A Systematic Review on Transplantation Studies of the Retinal Pigment Epithelium in Animal Models. Int J Mol Sci 2020; 21: 2719 DOI: 10.3390/ijms21082719.
• 12 Yin L, Greenberg K, Hunter JJ. et al. Intravitreal injection of AAV2 transduces macaque inner retina. Invest Ophthalmol Vis Sci 2011; 52: 2775-2783 DOI: 10.1167/iovs.10-6250.
• 13 Fan N, Lai L. Genetically modified pig models for human diseases. J Genet Genomics 2013; 40: 67-73 DOI: 10.1016/j.jgg.2012.07.014.
• 14 Moshiri A, Chen R, Kim S. et al. A nonhuman primate model of inherited retinal disease. J Clin Invest 2019; 129: 863-874 DOI: 10.1172/JCI123980.
• 15 Rodieck RW. The Vertebrate Retina: Principles of Structure and Function. Oxford: W. H. Freeman; 1973
• 16 Zeiss CJ. Animals as models of age-related macular degeneration: an imperfect measure of the truth. Vet Pathol 2010; 47: 396-413 DOI: 10.1177/0300985809359598.
• 17 Kubo E, Kumamoto Y, Tsuzuki S. et al. Axial Length, Myopia, and the Severity of Lens Opacity at the Time of Cataract Surgery. Arch Ophthalmol 2006; 124: 1586-1590 DOI: 10.1001/archopht.124.11.1586.
• 18 Groot ALW, Lissenberg-Witte BI, van Rijn LJ. et al. Meta-analysis of ocular axial length in newborns and infants up to 3 years of age. Surv Ophthalmol 2022; 67: 342-352 DOI: 10.1016/j.survophthal.2021.05.010.
• 19 Bach A, Villegas VM, Gold AS. et al. Axial length development in children. Int J Ophthalmol 2019; 12: 815-819 DOI: 10.18240/ijo.2019.05.18.
• 20 Qiao-Grider Y, Hung LF, Kee CS. et al. Normal ocular development in young rhesus monkeys (Macaca mulatta). Vision Res 2007; 47: 1424-1444 DOI: 10.1016/j.visres.2007.01.025.
• 21 Troilo D, Howland HC, Judge SJ. Visual optics and retinal cone topography in the common marmoset (Callithrix jacchus). Vision Res 1993; 33: 1301-1310 DOI: 10.1016/0042-6989(93)90038-x.
• 22 Reichel FF, Peters T, Wilhelm B. et al. Humoral Immune Response After Intravitreal But Not After Subretinal AAV8 in Primates and Patients. Invest Ophthalmol Vis Sci 2018; 59: 1910-1915 DOI: 10.1167/iovs.17-22494.
• 23 Reichel FF, Dauletbekov DL, Klein R. et al. AAV8 Can Induce Innate and Adaptive Immune Response in the Primate Eye. Mol Ther 2017; 25: 2648-2660 DOI: 10.1016/j.ymthe.2017.08.018.
• 24 Peterson SM, McGill TJ, Puthussery T. et al. Bardet-Biedl Syndrome in rhesus macaques: A nonhuman primate model of retinitis pigmentosa. Exp Eye Res 2019; 189: 107825 DOI: 10.1016/j.exer.2019.107825.
• 25 Matsumoto B, Blanks JC, Ryan SJ. Topographic variations in the rabbit and primate internal limiting membrane. Invest Ophthalmol Vis Sci 1984; 25: 71-82
• 26 Ye GJ, Budzynski E, Sonnentag P. et al. Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia. Hum Gene Ther Clin Dev 2016; 27: 37-48 DOI: 10.1089/humc.2015.164.
• 27 Takahashi K, Igarashi T, Miyake K. et al. Improved Intravitreal AAV-Mediated Inner Retinal Gene Transduction after Surgical Internal Limiting Membrane Peeling in Cynomolgus Monkeys. Mol Ther 2017; 25: 296-302 DOI: 10.1016/j.ymthe.2016.10.008.
• 28 Seok J, Warren HS, Cuenca AG. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 2013; 110: 3507-3512 DOI: 10.1073/pnas.1222878110.
• 29 Rogers J, Gibbs RA. Comparative primate genomics: emerging patterns of genome content and dynamics. Nat Rev Genet 2014; 15: 347-359 DOI: 10.1038/nrg3707.
• 30 Ru Q, Li W, Wang X. et al. Preclinical study of rAAV2-sTRAIL: pharmaceutical efficacy, biodistribution and safety in animals. Cancer Gene Ther 2017; 24: 251-258 DOI: 10.1038/cgt.2017.12.
• 31 Warren WC, Harris RA, Haukness M. et al. Sequence diversity analyses of an improved rhesus macaque genome enhance its biomedical utility. Science 2020; 370: eabc6617 DOI: 10.1126/science.abc6617.
• 32 Ikeda Y, Nishiguchi KM, Miya F. et al. Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa. Invest Ophthalmol Vis Sci 2018; 59: 826-830 DOI: 10.1167/iovs.17-22958.
• 33 Merker HJ, Heger W, Sames K. et al. Embryotoxic effects of thalidomide-derivatives in the non-human primate Callithrix jacchus. I. Effects of 3-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine (EM12) on skeletal development. Arch Toxicol 1988; 61: 165-179 DOI: 10.1007/BF00316631.
• 34 Janik E, Niemcewicz M, Ceremuga M. et al. Various Aspects of a Gene Editing System-CRISPR-Cas9. Int J Mol Sci 2020; 21: 9604 DOI: 10.3390/ijms21249604.
• 35 Balls M, Goldberg AM, Fentem JH. et al. The three Rs: the way forward: the report and recommendations of ECVAM Workshop 11. Altern Lab Anim 1995; 23: 838-866 DOI: 10.1177/026119299502300614.