Photorezeptortransplantation in die degenerative Netzhaut

Zusammenfassung

Sehbeeinträchtigungen und Erblindung aufgrund des Verlusts von Photorezeptoren stellen einen der Hauptgründe für Behinderungen in industrialisierten Gesellschaften dar. Während Stäbchenphotorezeptoren Seheindrücke unter schwachen Lichtverhältnissen vermitteln, liefern Zapfenphotorezeptoren fokussierte visuelle Eindrücke bei Tageslicht und erlauben die Wahrnehmung von Farben. Verschiedene therapeutische Strategien, zu denen auch zellbasierte Interventionen zählen, werden derzeit zur Behandlung eines Sehverlusts entwickelt. Während der letzten Dekade konnten große Fortschritte im Ersatz von Photorezeptoren in vorklinischen Tiermodellen erzielt werden. Dies beinhaltete die Klärung notwendiger Voraussetzungen, wie dem optimalen ontogenetischen Stadium für transplantierbare Photorezeptoren, zellspezifische Anreicherungsmethoden und robuste Transplantationstechniken. Außerdem konnten erste Studien Hinweise auf funktionale Verbesserungen nach Photorezeptortransplantation in Mausmodelle mit retinaler Dysfunktion liefern. Des Weiteren erlauben bedeutende Fortschritte in der Zellkulturtechnik die Generierung von photorezeptorenthaltenden retinalen Organoiden, die aus pluripotenten Stammzellen gewonnen werden und eine theoretisch unbegrenzte Quelle zur Produktion von Photorezeptortransplantaten darstellen. Interessanterweise könnte der kürzlich beschriebene Transfer von zytoplasmatischem Material zwischen Spender- und Empfängerphotorezeptoren eine weitere Behandlungsoption für Ansätze zur Zelltransplantation darstellen. In dieser Übersicht fokussieren wir uns auf die wichtigsten Entwicklungen innerhalb des Feldes der Photorezeptortransplantation, wobei wir Fortschritte, Herausforderungen und Hürden zur Entwicklung von Photorezeptortransplantationen hin zu klinischen Anwendungen diskutieren.

Abstract

Vision impairment and blindness due to photoreceptor loss represents one of the major causes for disability in industrialized societies. Whereas rod photoreceptors allow vision under dim light conditions, cone photoreceptors provide high-acuity vision in daylight conditions and color detection. Several therapeutic strategies are currently developed to repair vision loss, including cell-based interventions. Within the last decade, major progress regarding the replacement of photoreceptors by transplantation has been made in pre-clinical animal models. This includes defining the necessary conditions, like the optimal ontogenetic stage of transplantable donor photoreceptors, cell-specific enrichment procedures and robust transplantation technologies. Moreover, first studies provided evidence for functional improvements by photoreceptor transplantation in mouse models of retinal dysfunction. Furthermore, advances in cell culture technology were made by introducing methods to generate photoreceptor-containing retinal organoids, derived from pluripotent stem cells, that provide theoretically unlimited sources for the production of photoreceptor transplants. Interestingly, the recently identified transfer of cytoplasmic material between donor and host photoreceptors might represent an additional treatment option for cell transplantation approaches. Within this review, we focus on the main developments within the photoreceptor transplantation field and discuss important achievements, challenges and hurdles to develop photoreceptor transplantation towards clinical applications.

Schlüsselwörter

Netzhaut - Netzhautdegeneration - Photorezeptor - Transplantation - Stammzelle

Key words

retina - retinal degeneration - photoreceptor - transplantation - stem cell

• Literatur

• 1 Korb CA, Kottler UB, Wolfram C, Hoehn R, Schulz A, Zwiener I. et al. Prevalence of age-related macular degeneration in a large European cohort: Results from the population-based Gutenberg Health Study. Graefes Arch Clin Exp Ophthalmol 2014; 252: 1403-1411
• 2 Smith W, Assink J, Klein R. et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology 2001; 108: 697-704
• 3 World Health Organization (WHO). Visual impairment and blindness. Fact Sheet No. 282. Im Internet: http://www.who.int/mediacentre/factsheets/fs282/en/ Stand: 03.11.2016
• 4 Trifunovic D, Sahaboglu A, Kaur J. et al. Neuroprotective strategies for the treatment of inherited photoreceptor degeneration. Curr Mol Med 2012; 12: 598-612
• 5 Acland GM, Aguirre GD, Ray J. et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001; 28: 92-95
• 6 Lazic R, Gabric N. Intravitreally administered bevacizumab (Avastin) in minimally classic and occult choroidal neovascularization secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2006; 245: 68-73
• 7 Busskamp V, Duebel J, Balya D. et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 2010; 329: 413-417
• 8 Lewis PM, Ayton LN, Guymer RH. et al. Advances in implantable bionic devices for blindness: a review: Advances in bionic devices for blindness. ANZ J Surg 2016; 86: 654-659
• 9 Jones BW, Pfeiffer RL, Ferrell WD. et al. Retinal remodeling in human retinitis pigmentosa. Exp Eye Res 2016; 150: 149-165
• 10 Reh TA. Photoreceptor transplantation in late stage retinal degeneration. Invest Ophthalmol Vis Sci 2016; 57: ORSFg1-7
• 11 da Cruz L, Dorn JD, Humayun MS. et al. Five-year safety and performance results from the Argus II retinal prosthesis system clinical trial. Ophthalmology 2016; 123: 2248-2254
• 12 Forrester JV. Privilege revisited: an evaluation of the eyeʼs defence mechanisms. Eye (Lond) 2009; 23: 756-766
• 13 Stein-Streilein J. Immune regulation and the eye. Trends Immunol 2008; 29: 548-554
• 14 Eiraku M, Takata N, Ishibashi H. et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 2011; 472: 51-55
• 15 Nakano T, Ando S, Takata N. et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 2012; 10: 771-785
• 16 Pearson RA, Gonzalez-Cordero A, West EL. et al. Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors. Nat Commun 2016; 7: 13029
• 17 Santos-Ferreira T, Llonch S, Borsch O. et al. Retinal transplantation of photoreceptors results in donor-host cytoplasmic exchange. Nat Commun 2016; 7: 13028
• 18 Singh MS, Balmer J, Barnard AR. et al. Transplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion. Nat Commun 2016; 7: 13537
• 19 del Cerro M, Notter MF, Grover DA. et al. Retinal transplants for cell replacement in phototoxic retinal degeneration. Prog Clin Biol Res 1988; 314: 673-686
• 20 del Cerro M, Notter MFD, del Cerro C. et al. Intraretinal transplantation for rod-cell replacement in light-damaged retinas. Neural Plast 1989; 1: 1-10
• 21 Gouras P, Du J, Gelanze M. et al. Transplantation of photoreceptors labeled with tritiated thymidine into RCS rats. Invest Ophthalmol Vis Sci 1991; 32: 1704-1707
• 22 Gouras P, Du J, Kjeldbye H. et al. Transplanted photoreceptors identified in dystrophic mouse retina by a transgenic reporter gene. Invest Ophthalmol Vis Sci 1991; 32: 3167-3174
• 23 Gouras P, Du J, Gelanze M. et al. Survival and synapse formation of transplanted rat rods. J Neural Transplant Plast 1991; 2: 91-100
• 24 Gouras P, Du J, Kjeldbye H. et al. Long-term photoreceptor transplants in dystrophic and normal mouse retina. Invest Ophthalmol Vis Sci 1994; 35: 3145-3153
• 25 Du J, Gouras P, Kjeldbye H. et al. Monitoring photoreceptor transplants with nuclear and cytoplasmic markers. Exp Neurol 1992; 115: 79-86
• 26 Coles BLK, Angenieux B, Inoue T. et al. Facile isolation and the characterization of human retinal stem cells. Proc Natl Acad Sci U S A 2004; 101: 15772-15777
• 27 Klassen HJ, Ng TF, Kurimoto Y. et al. Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Invest Ophthalmol Vis Sci 2004; 45: 4167-4173
• 28 Merhi-Soussi F, Angénieux B, Canola K. et al. High yield of cells committed to the photoreceptor fate from expanded mouse retinal stem cells. Stem Cells 2006; 24: 2060-2070
• 29 Seiler MJ, Aramant RB. Cell replacement and visual restoration by retinal sheet transplants. Prog Retin Eye Res 2012; 31: 661-687
• 30 Ballios BG, Cooke MJ, Donaldson L. et al. A hyaluronan-based injectable hydrogel improves the survival and integration of stem cell progeny following transplantation. Stem Cell Reports 2015; 4: 1031-1045
• 31 Cicero SA, Johnson D, Reyntjens S. et al. Cells previously identified as retinal stem cells are pigmented ciliary epithelial cells. Proc Natl Acad Sci U S A 2009; 106: 6685-6690
• 32 Czekaj M, Haas J, Gebhardt M. et al. In vitro expanded stem cells from the developing retina fail to generate photoreceptors but differentiate into myelinating oligodendrocytes. PLoS One 2012; 7: e41798
• 33 Gualdoni S, Baron M, Lakowski J. et al. Adult ciliary epithelial cells, previously identified as retinal stem cells with potential for retinal repair, fail to differentiate into new rod photoreceptors. Stem Cells 2010; 28: 1048-1059
• 34 Ringuette R, Wang Y, Atkins M. et al. Combinatorial hedgehog and mitogen signaling promotes the in vitro expansion but not retinal differentiation potential of retinal progenitor cells. Invest Ophthalmol Vis Sci 2014; 55: 43-54
• 35 MacLaren RE, Pearson RA, MacNeil A. et al. Retinal repair by transplantation of photoreceptor precursors. Nature 2006; 444: 203-207
• 36 Bartsch U, Oriyakhel W, Kenna PF. et al. Retinal cells integrate into the outer nuclear layer and differentiate into mature photoreceptors after subretinal transplantation into adult mice. Exp Eye Res 2008; 86: 691-700
• 37 Pearson RA, Barber AC, Rizzi M. et al. Restoration of vision after transplantation of photoreceptors. Nature 2012; 485: 99-103
• 38 Eberle D, Kurth T, Santos-Ferreira T. et al. Outer segment formation of transplanted photoreceptor precursor cells. PLoS One 2012; 7: e46305
• 39 Li T, Snyder WK, Olsson JE. et al. Transgenic mice carrying the dominant rhodopsin mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer segments. Proc Natl Acad Sci U S A 1996; 93: 14176-14181
• 40 Gust J, Reh TA. Adult donor rod photoreceptors integrate into the mature mouse retina. Invest Ophthalmol Vis Sci 2011; 52: 5266-5272
• 41 Zayas-Santiago A, Derwent JJK. Preservation of intact adult rat photoreceptors in vitro: Study of dissociation techniques and the effect of light. Mol Vis 2009; 15: 1
• 42 Yao J, Feathers KL, Khanna H. et al. XIAP therapy increases survival of transplanted rod precursors in a degenerating host retina. Invest Ophthalmol Vis Sci 2011; 52: 1567-1572
• 43 Barber AC, Hippert C, Duran Y. et al. Repair of the degenerate retina by photoreceptor transplantation. Proc Natl Acad Sci U S A 2013; 110: 354-359
• 44 Lakowski J, Han YT, Pearson R. et al. Effective transplantation of photoreceptor precursor cells selected via cell surface antigen expression. Stem Cells 2011; 29: 1391-1404
• 45 Warre-Cornish K, Barber AC, Sowden JC. et al. Migration, integration and maturation of photoreceptor precursors following transplantation in the mouse retina. Stem Cells Dev 2014; 23: 941-954
• 46 Eberle D, Schubert S, Postel K. et al. Increased Integration of transplanted cd73-positive photoreceptor precursors into adult mouse retina. Invest Ophthalmol Vis Sci 2011; 52: 6462-6471
• 47 Lakowski J, Gonzalez-Cordero A, West EL. et al. Transplantation of photoreceptor precursors isolated via a cell surface biomarker panel from embryonic stem cell-derived selfforming retina: transplanting ESC-derived rods via surface markers. Stem Cells 2015; 33: 2469-2482
• 48 Kaewkhaw R, Kaya KD, Brooks M. et al. Transcriptome dynamics of developing photoreceptors in three-dimensional retina cultures recapitulates temporal sequence of human cone and rod differentiation revealing cell surface markers and gene networks: transcriptome of developing human photoreceptors. Stem Cells 2015; 33: 3504-3518
• 49 Postel K, Bellmann J, Splith V. et al. Analysis of cell surface markers specific for transplantable rod photoreceptors. Mol Vis 2013; 19: 2058-2067
• 50 Carter-Dawson LD, Lavail MM. Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. J Comp Neurol 1979; 188: 245-262
• 51 Akimoto M, Cheng H, Zhu D. et al. Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proc Natl Acad Sci U S A 2006; 103: 3890-3895
• 52 Lakowski J, Baron M, Bainbridge J. et al. Cone and rod photoreceptor transplantation in models of the childhood retinopathy Leber congenital amaurosis using flow-sorted Crx-positive donor cells. Hum Mol Genet 2010; 19: 4545-4559
• 53 Mears AJ, Kondo M, Swain PK. et al. Nrl is required for rod photoreceptor development. Nat Genet 2001; 29: 447-452
• 54 Okabe M, Ikawa M, Kominami K. et al. Green miceʼas a source of ubiquitous green cells. FEBS Lett 1997; 407: 313-319
• 55 Chang B, Hawes NL, Hurd RE. et al. Retinal degeneration mutants in the mouse. Vision Res 2002; 42: 517-525
• 56 Chang B, Grau T, Dangel S. et al. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci U S A 2009; 106: 19581-19586
• 57 Santos-Ferreira T, Postel K, Stutzki H. et al. Daylight Vision Repair by Cell Transplantation. Stem Cells 2015; 33: 79-90
• 58 Singh MS, Charbel Issa P, Butler R. et al. Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation. Proc Natl Acad Sci U S A 2013; 110: 1101-1106
• 59 Zhong X, Gutierrez C, Xue T. et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat Commun 2014; 5: 4047
• 60 Völkner M, Zschätzsch M, Rostovskaya M. et al. Retinal organoids from pluripotent stem cells efficiently recapitulate retinogenesis. Stem Cell Reports 2016; 6: 525-538
• 61 Assawachananont J, Mandai M, Okamoto S. et al. Transplantation of embryonic and induced pluripotent stem cell-derived 3 d retinal sheets into retinal degenerative mice. Stem Cell Reports 2014; 2: 662-674
• 62 Decembrini S, Koch U, Radtke F. et al. Derivation of traceable and transplantable photoreceptors from mouse embryonic stem cells. Stem Cell Reports 2014; 2: 853-865
• 63 Gonzalez-Cordero A, West EL, Pearson RA. et al. Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nat Biotechnol 2013; 31: 741-747
• 64 Santos-Ferreira T, Völkner M, Borsch O. et al. Stem cell–derived photoreceptor transplants differentially integrate into mouse models of cone-rod dystrophy. Invest Ophthalmol Vis Sci 2016; 57: 3509-3520
• 65 Lamba DA, Gust J, Reh TA. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell 2009; 4: 73-79
• 66 Lamba DA, McUsic A, Hirata RK. et al. Generation, purification and transplantation of photoreceptors derived from human induced pluripotent stem cells. PLoS One 2010; 5: e8763
• 67 Shirai H, Mandai M, Matsushita K. et al. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc Natl Acad Sci U S A 2016; 113: E81-E90
• 68 Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003; 425: 968-973
• 69 Odendahl M, Grigoleit GU, Boenig H. et al. Clinical-scale isolation of “minimally manipulated” cytomegalovirus-specific donor lymphocytes for the treatment of refractory cytomegalovirus disease. Cytotherapy 2014; 16: 1245-1256
• 70 Wiley LA, Burnight ER, DeLuca AP. et al. cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness. Sci Rep 2016; 6: 30742
• 71 Sugita S, Iwasaki Y, Makabe K. et al. Successful transplantation of retinal pigment epithelial cells from MHC homozygote iPSCs in MHC-matched models. Stem Cell Reports 2016; 7: 635-648
• 72 Andrews PW, Cavagnaro J, Deans R. et al. Harmonizing standards for producing clinical-grade therapies from pluripotent stem cells. Nat Biotechnol 2014; 32: 724-726
• 73 Baghbaderani BA, Tian X, Neo BH. et al. cGMP-manufactured human induced pluripotent stem cells are available for pre-clinical and clinical applications. Stem Cell Reports 2015; 5: 647-659
• 74 Salomonis N, Dexheimer PJ, Omberg L. et al. Integrated genomic analysis of diverse induced pluripotent stem cells from the progenitor cell biology consortium. Stem Cell Reports 2016; 7: 110-125
• 75 Mandai M, Fujii M, Hashiguchi T. et al. iPSC-derived retina transplants improve vision in rd1 end-stage retinal-degeneration mice. Stem Cell Reports 2017; 8: 69-83
• 76 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