Trockene AMD – zelluläre und gentherapeutische Behandlungsansätze

Zusammenfassung

Die zunehmende Anzahl degenerativer Erkrankungen ist zurückzuführen auf unsere immer älter werdende Gesellschaft sowie die diffizile Etablierung definierter Therapiekonzepte. Im Fall der trockenen altersbedingten Makuladegeneration (AMD) und dem späten Stadium der geografischen Atrophie (GA) existieren bislang lediglich verschiedene Behandlungsformen, die eine verzögerte Progression des Krankheitsverlaufs bewirken, jedoch keine Therapie, die in der Lage ist, die geschädigten retinalen Pigmentepithel (RPE) und/oder Photorezeptorzellen wiederherzustellen. Demgegenüber verfolgen zell- und/oder genbasierte Behandlungsansätze das Ziel der Regeneration des geschädigten Gewebes und/oder der kontinuierlichen Sezernierung zellschützender Agenzien. Der Artikel beschreibt die aktuell in der klinischen Austestung befindlichen Ansätze, die auf der Verwendung von zellbasierten Drug-Delivery-Systemen, Stammzellen unterschiedlichen Ursprungs und virusbasierten Gentherapieverfahren beruhen. Abschließend wird ein Ausblick auf verschiedene Therapieweiterentwicklungen gegeben und es werden eigene Forschungsarbeiten vorgestellt, die auf einer Kombination aus Pigmentepithelzelltransplantation und additiver nicht viraler Gentherapie zur Behandlung degenerativer Netzhauterkrankungen basieren.

Abstract

The growing incidence of neurodegenerative diseases is based on our increasingly aging society as well as the difficulties in establishing defined therapy regimens. For dry age-related macular degeneration (AMD) and the later stage of geographic atrophy (GA), various treatment options exist that only decelerate the progression of the disease. However, no therapy is currently available that can restore the degenerated retinal pigment epithelium (RPE) and/or photoreceptor cells. Cellular and gene-based approaches aim for the regeneration of the degenerated cells and/or the continuous secretion of cell-protecting agents. The article describes the approaches that are currently being investigated in different clinical trials. These trials are based on the use of cell-based drug delivery systems, stem cells of different origins as well as virus-mediated gene therapy approaches. Finally, we give an overview of ongoing therapeutic developments and present our own research activities, which consist of a combination of pigment epithelial cell transplantation and additive non-viral gene therapy to treat retinal degenerative diseases.

Schlüsselwörter

trockene AMD - zelluläre Therapie - Kapsel-Zell-Implantat - humane embryonale Stammzellen - autologe Knochenmarkstammzellen - additive Gentherapie

Key words

dry AMD - cellular therapy - encapsulated cell technology - human embryonic stem cells - autologous bone marrow stem cells - additive gene therapy

• Literatur

• 1 Wong WL, Su X, Li X. 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: e106-e116 doi:10.1016/S2214-109X(13)70145-1
• 2 Algvere PV, Berglin L, Gouras P. et al. Transplantation of RPE in age-related macular degeneration: observations in disciform lesions and dry RPE atrophy. Graefes Arch Clin Exp Ophthalmol 1997; 235: 149-158
• 3 Algvere PV, Gouras P, Dafgård Kopp E. Long-term outcome of RPE allografts in non-immunosuppressed patients with AMD. Eur J Ophthalmol 1999; 9: 217-230
• 4 Joussen AM, Heussen FM, Joeres S. et al. Autologous translocation of the choroid and retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 2006; 142: 17-30 doi:10.1016/j.ajo.2006.01.090
• 5 Eckardt C, Eckardt U. Macular translocation in nonexudative age-related macular degeneration. Retina 2002; 22: 786-794
• 6 Cahill MT, Mruthyunjaya P, Bowes Rickman C. et al. Recurrence of retinal pigment epithelial changes after macular translocation with 360 degrees peripheral retinectomy for geographic atrophy. Arch Ophthal 2005; 123: 935-938 doi:10.1001/archopht.123.7.935
• 7 Schwartz SD, Hubschman JP, Heilwell G. et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012; 379: 713-720 doi:10.1016/S0140-6736(12)60028-2
• 8 Schwartz SD, Regillo CD, Lam BL. et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardtʼs macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet 2015; 385: 509-516 doi:10.1016/S0140-6736(14)61376-3
• 9 Song WK, Park KM, Kim HJ. et al. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients. Stem Cell Reports 2015; 4: 860-872 doi:10.1016/j.stemcr.2015.04.005
• 10 Schwartz SD, Tan G, Hosseini H. et al. Subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium for the treatment of macular degeneration: an assessment at 4 years. Invest Ophthalmol Vis Sci 2016; 57: ORSFc1-9 doi:10.1167/iovs.15-18681
• 11 Park SS, Bauer G, Abedi M. et al. Intravitreal autologous bone marrow CD34+ cell therapy for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trial findings. Invest Ophthalmol Vis Sci 2014; 56: 81-89 doi:10.1167/iovs.14-15415
• 12 Cotrim CC, Toscano L, Messias A. et al. Intravitreal use of bone marrow mononuclear fraction containing CD34(+) stem cells in patients with atrophic age-related macular degeneration. Clin Ophthalmol 2017; 11: 931-938 doi:10.2147/OPTH.S133502
• 13 Zhang K, Hopkins JJ, Heier JS. et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A 2011; 108: 6241-6245 doi:10.1073/pnas.1018987108
• 14 Faktorovich EG, Steinberg RH, Yasumura D. et al. Photoreceptor degeneration in inherited retinal dystrophy delayed by basic fibroblast growth factor. Nature 1990; 347: 83-86 doi:10.1038/347083a0
• 15 Cayouette M, Behn D, Sendtner M. et al. Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse. J Neurosci 1998; 18: 9282-9293
• 16 LaVail MM, Unoki K, Yasumura D. et al. Multiple growth factors, cytokines, and neurotrophins rescue photoreceptors from the damaging effects of constant light. Proc Natl Acad Sci U S A 1992; 89: 11249-11253
• 17 Li S, Sato K, Gordon WC. et al. Ciliary neurotrophic factor (CNTF) protects retinal cone and rod photoreceptors by suppressing excessive formation of the visual pigments. J Biol Chem 2018; 293: 15256-15268 doi:10.1074/jbc.RA118.004008
• 18 Kauper K, McGovern C, Sherman S. et al. Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases. Invest Ophthalmol Vis Sci 2012; 53: 7484-7491 doi:10.1167/iovs.12-9970
• 19 Klimanskaya I, Chung Y, Becker S. et al. Human embryonic stem cell lines derived from single blastomeres. Nature 2006; 444: 481-485 doi:10.1038/nature05142
• 20 McGill TJ, Bohana-Kashtan O, Stoddard JW. et al. Long-term efficacy of GMP grade xeno-free hESC-derived RPE cells following transplantation. Transl Vis Sci Technol 2017; 6: 17 doi:10.1167/tvst.6.3.17
• 21 Kashani AH, Lebkowski JS, Rahhal FM. et al. A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci Transl Med 2018; 10: eaao4097 doi:10.1126/scitranslmed.aao4097
• 22 Ludwig CA, Leng T. Retinotomy closure following subretinal stem cell transplant with a 30-gauge needle. Ophthalmic Surg Lasers Imaging Retina 2016; 47: 869-873 doi:10.3928/23258160-20160901-12
• 23 Weiss JN, Levy S, Benes SC. Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a case report of improvement in relapsing auto-immune optic neuropathy. Neural Regen Res 2015; 10: 1507-1515 doi:10.4103/1673-5374.165525
• 24 Weiss JN, Levy S, Malkin A. Stem Cell Ophthalmology Treatment Study (SCOTS) for retinal and optic nerve diseases: a preliminary report. Neural Regen Res 2015; 10: 982-988 doi:10.4103/1673-5374.158365
• 25 Weiss JN, Benes SC, Levy S. Stem Cell Ophthalmology Treatment Study (SCOTS): improvement in serpiginous choroidopathy following autologous bone marrow derived stem cell treatment. Neural Regen Res 2016; 11: 1512-1516 doi:10.4103/1673-5374.191229
• 26 Weiss JN, Levy S, Benes SC. Stem Cell Ophthalmology Treatment Study (SCOTS): bone marrow-derived stem cells in the treatment of Leberʼs hereditary optic neuropathy. Neural Regen Res 2016; 11: 1685-1694 doi:10.4103/1673-5374.193251
• 27 Ho AC, Chang TS, Samuel M. et al. Experience with a subretinal cell-based therapy in patients with geographic atrophy secondary to age-related macular degeneration. Am J Ophthalmol 2017; 179: 67-80 doi:10.1016/j.ajo.2017.04.006
• 28 Lund RD, Wang S, Lu B. et al. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007; 25: 602-611 doi:10.1634/stemcells.2006-0308
• 29 Koh S, Chen WJ, Dejneka NS. et al. Subretinal human umbilical tissue-derived cell transplantation preserves retinal synaptic connectivity and attenuates Müller glial reactivity. J Neurosci 2018; 38: 2923-2943 doi:10.1523/JNEUROSCI.1532-17.2018
• 30 de Smet MD, Lynch JL, Dejneka NS. et al. A subretinal cell delivery method via suprachoroidal access in minipigs: safety and surgical outcomes. Invest Ophthalmol Vis Sci 2018; 59: 311-320 doi:10.1167/iovs.17-22233
• 31 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: e19078 doi:10.1371/journal.pone.0019078
• 32 Plaza Reyes A, Petrus-Reurer S, Antonsson L. et al. Xeno-free and defined human embryonic stem cell-derived retinal pigment epithelial cells functionally integrate in a large-eyed preclinical model. Stem Cell Reports 2016; 6: 9-17 doi:10.1016/j.stemcr.2015.11.008
• 33 Croze RH, Thi WJ, Clegg DO. ROCK inhibition promotes attachment, proliferation, and wound closure in human embryonic stem cell-derived retinal pigmented epithelium. Transl Vis Sci Technol 2016; 5: 7 doi:10.1167/tvst.5.6.7
• 34 Petrus-Reurer S, Bartuma H, Aronsson M. et al. Integration of subretinal suspension transplants of human embryonic stem cell-derived retinal pigment epithelial cells in a large-eyed model of geographic atrophy. Invest Ophthalmol Vis Sci 2017; 58: 1314-1322 doi:10.1167/iovs.16-20738
• 35 Ilmarinen T, Thieltges F, Hongisto H. et al. Survival and functionality of xeno-free human embryonic stem cell-derived retinal pigment epithelial cells on polyester substrate after transplantation in rabbits. Acta Ophthalmol 2018;
• 36 Buchholz DE, Hikita ST, Rowland TJ. et al. Derivation of functional retinal pigmented epithelium from induced pluripotent stem cells. Stem Cells 2009; 27: 2427-2434 doi:10.1002/stem.189
• 37 Takahashi K, Tanabe K, Ohnuki M. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861-872 doi:10.1016/j.cell.2007.11.019
• 38 Mandai M, Watanabe A, Kurimoto Y. et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N Engl J Med 2017; 376: 1038-1046 doi:10.1056/NEJMoa1608368
• 39 Hallam D, Collin J, Bojic S. et al. An induced pluripotent stem cell patient specific model of complement factor H (Y402H) polymorphism displays characteristic features of age-related macular degeneration and indicates a beneficial role for UV light exposure. Stem Cells 2017; 35: 2305-2320 doi:10.1002/stem.2708
• 40 Saini JS, Corneo B, Miller JD. et al. Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell 2017; 20: 635-647.e7 doi:10.1016/j.stem.2016.12.015
• 41 Eyjolfsdottir H, Eriksdotter M, Linderoth B. et al. Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimerʼs disease patients: application of a second-generation encapsulated cell biodelivery device. Alzheimers Res Ther 2016; 8: 30 doi:10.1186/s13195-016-0195-9
• 42 Mátés L, Chuah MK, Belay E. et al. Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates. Nat Genet 2009; 41: 753-761 doi:10.1038/ng.343
• 43 Fjord-Larsen L, Kusk P, Emerich DF. et al. Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer. Gene Ther 2012; 19: 1010-1017 doi:10.1038/gt.2011.178
• 44 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: 4787-4796 doi:10.1167/iovs.12-9951
• 45 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: 302-314 doi:10.1016/j.omtn.2017.02.002
• 46 Falk T, Gonzalez RT, Sherman SJ. The yin and yang of VEGF and PEDF: multifaceted neurotrophic factors and their potential in the treatment of Parkinsonʼs disease. Int J Mol Sci 2010; 11: 2875-2900 doi:10.3390/ijms11082875
• 47 Thumann G, Aisenbrey S, Schraermeyer U. et al. Transplantation of autologous iris pigment epithelium after removal of choroidal neovascular membranes. Arch Ophthal 2000; 118: 1350-1355
• 48 Aisenbrey S, Lafaut BA, Szurman P. et al. Iris pigment epithelial translocation in the treatment of exudative macular degeneration: a 3-year follow-up. Arch Ophthal 2006; 124: 183-188 doi:10.1001/archopht.124.2.183
• 49 Comitato A, Subramanian P, Turchiano G. et al. Pigment epithelium-derived factor hinders photoreceptor cell death by reducing intracellular calcium in the degenerating retina. Cell Death Dis 2018; 9: 560 doi:10.1038/s41419-018-0613-y
• 50 Liu Y, Tao L, Fu X. et al. BDNF protects retinal neurons from hyperglycemia through the TrkB/ERK/MAPK pathway. Mol Med Rep 2013; 7: 1773-1778 doi:10.3892/mmr.2013.1433
• 51 Osborne A, Khatib TZ, Songra L. et al. Neuroprotection of retinal ganglion cells by a novel gene therapy construct that achieves sustained enhancement of brain-derived neurotrophic factor/tropomyosin-related kinase receptor-B signaling. Cell Death Dis 2018; 9: 1007 doi:10.1038/s41419-018-1041-8
• 52 Yue P, Miao W, Gao L. et al. Ultrasound-triggered effects of the microbubbles coupled to GDNF plasmid-loaded PEGylated liposomes in a rat model of Parkinsonʼs disease. Front Neurosci 2018; 12: 222 doi:10.3389/fnins.2018.00222
• 53 Dalkara D, Kolstad KD, Guerin KI. et al. AAV mediated GDNF secretion from retinal glia slows down retinal degeneration in a rat model of retinitis pigmentosa. Mol Ther 2011; 19: 1602-1608 doi:10.1038/mt.2011.62