Therapieansätze für erbliche Netzhauterkrankungen: von den Genen bis zum Chip

Zusammenfassung

Derzeit werden verschiedene Strategien für die Behandlung erblich bedingter Photorezeptordegenerationen verfolgt. Die Mehrzahl dieser Ansätze sind in der Entwicklungsphase präklinischer oder klinischer Studien mit einem noch zu leistenden erheblichen Entwicklungsbedarf. Erbliche Netzhauterkrankungen sind genetisch und bezogen auf das Einsetzen klinischer Symptome und ihren Verlauf sehr heterogen. Dies macht den Schritt von der präklinischen Erprobung zur klinischen Studie schwierig und lässt überdies bei einigen früh einsetzenden Erkrankungen einen nur sehr begrenzten zeitlichen Rahmen für eine effektive Therapie. Die meisten bereits in der Entwicklung begriffenen gentherapeutischen Verfahren zielen auf die Rekonstitution physiologisch essenzieller Funktionen in retinalem Pigmentepithel und Photorezeptor. Die Neuroprotektion dagegen zielt auf den Zellerhalt von retinalen Zellen, die der Gefahr unterliegen, krankheitsbedingt zu degenerieren. Zellbasierte Ansätze wie z. B. die Zelltransplantation zielen auf den Ersatz verloren gegangener retinaler Zellen ab. Implantationsverfahren von elektronischen Prothesen und die Optogenetik zielen auf den künstlichen Ersatz verloren gegangener sensorischer Leistungen des Auges. Dieser Artikel soll einen Einblick in derzeit verfolgte therapeutische Strategien zur Behandlung erblicher Netzhauterkrankungen geben. Während pharmakologische Ansätze und supportive Nahrungsergänzungsmittel nur kurz besprochen werden, liegt der Schwerpunkt dieser Übersicht auf molekularen und prothetischen Ansätzen.

Abstract

Different strategies for the treatment of inherited photoreceptor degeneration are currently being investigated, with each of these approaches facing specific challenges. Gene therapy, for instance, may be feasible only for genetically well-defined pathologies. However, inherited retinal disorders are genetically highly heterogeneous and early onset disorders may restrict the therapeutic window. The majority of currently developed molecular approaches aim at the reconstitution of physiologically important functions in RPE and photoreceptor. Neuroprotection attempts to prolong cell survival and proper function via sustained delivery systems that fulfil a long-term dynamic reservoir function for therapeutic neuroprotective compounds. Cell-based approaches include replacement strategies such as cell transplantation, the implantation of prosthetic devices or optogenetics. They aim at replacing lost neurosensory functions of the retina. This short review aims at providing an insight into current therapeutic strategies and future treatment options for retinal disorders. Pharmacological and nutritional support strategies are only briefly discussed as we focus here on molecular and prosthetic therapeutic approaches.

Schlüsselwörter

erbliche Netzhautdegeneration - Retinitis pigmentosa (RP) - Neuroprotektion - translationale Medizin - Therapieentwicklung - Lebersche Kongenitale Amaurose (LCA)

Key words

hereditary retinal disorders - retinitis pigmentosa (RP) - neuroprotection - translational medicine - therapy development - Leberʼs congenital amaurosis (LCA)

• Literatur

• 1 Congdon N, OʼColmain B, Klaver CC et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004; 122: 477-485
• 2 Jones BW, Marc RE. Retinal remodeling during retinal degeneration. Exp Eye Res 2005; 81: 123-137
• 3 Sancho-Pelluz J, Arango-Gonzalez B, Kustermann S et al. Photoreceptor cell death mechanisms in inherited retinal degeneration. Mol Neurobiol 2008; 38: 253-269
• 4 Samardzija M, Neuhauss SCF, Joly S et al. Animal models for retinal degeneration. In: Pang I-H, Clark AF, eds. Animal Models of retinal Disease. New York: The Humana Press Inc; 2010
• 5 Del Rio P, Irmler M, Arango-Gonzalez B et al. GDNF-induced osteopontin from Müller glial cells promotes photoreceptor survival in the Pde6b(rd1) mouse model of retinal degeneration. Glia 2011; 59: 821-832
• 6 Pinzon-Duarte G, Arango-Gonzalez B, Guenther E et al. Effects of brain-derived neurotrophic factor on cell survival, differentiation and patterning of neuronal connections and Müller glia cells in the developing retina. Eur J Neurosci 2004; 19: 1475-1484
• 7 Paquet-Durand F, Sanges D, McCall J et al. Photoreceptor rescue and toxicity induced by different calpain inhibitors. J Neurochem 2010; 115: 930-940
• 8 Arango-Gonzalez B, Cellerino A, Kohler K. Exogenous brain-derived neurotrophic factor (BDNF) reverts phenotypic changes in the retinas of transgenic mice lacking the BDNF Gene. Invest Ophthalmol Vis Sci 2009; 50: 1416-1422
• 9 Trifunovic D, Sahaboglu A, Kaur J et al. Neuroprotective strategies for the treatment of inherited photoreceptor degeneration. Curr Mol Med 2012; 12: 598-612
• 10 MacLaren RE, Pearson RA, MacNeil A et al. Retinal repair by transplantation of photoreceptor precursors. Nature 2006; 444: 203-207
• 11 Zrenner E. Fighting blindness with microelectronics. Sci Transl Med 2013; 5: 210ps16
• 12 Zrenner E, Bartz-Schmidt KU, Benav H et al. Subretinal electronic chips allow blind patients to read letters and combine them to words. Proc Biol Sci 2011; 278: 1489-1497
• 13 Julien S, Peters T, Ziemssen F et al. Implantation of ultrathin, biofunctionalized polyimide membranes into the subretinal space of rats. Biomaterials 2011; 32: 3890-3898
• 14 Singh MS, MacLaren RE. Stem cells as a therapeutic tool for the blind: biology and future prospects. Proc Biol Sci 2011; 278: 3009-3016
• 15 DFG. Entwicklung der Gentherapie – Stellungnahme der Senatskommission für Grundsatzfragen der Genforschung. In: Senatskommission für Grundsatzfragen der Genforschung, Hrsg. Mitteilung 5. Weinheim: Wiley-VCH; 2007: 1-77
• 16 Sahni JN, Angi M, Irigoyen C et al. Therapeutic challenges to retinitis pigmentosa: from neuroprotection to gene therapy. Curr Genomics 2011; 12: 276-284
• 17 Cepko CL. Emerging gene therapies for retinal degenerations. J Neurosci 2012; 32: 6415-6420
• 18 Maguire AM, High KA, Auricchio A et al. Age-dependent effects of RPE65 gene therapy for Leberʼs congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009; 374: 1597-1605
• 19 Acland GM, Aguirre GD, Bennett J et al. Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther 2005; 12: 1072-1082
• 20 Jacobson SG, Boye SL, Aleman TS et al. Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther 2006; 17: 845-858
• 21 Simonelli F, Maguire AM, Testa F et al. Gene therapy for Leberʼs congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 2010; 18: 643-650
• 22 Stieger K, Lorenz B. Gene therapy for vision loss – recent developments. Discov Med 2010; 10: 425-433
• 23 Barkana Y, Belkin M. Neuroprotection in ophthalmology: a review. Brain Res Bull 2004; 62: 447-453
• 24 Chaum E. Retinal neuroprotection by growth factors: a mechanistic perspective. J Cell Biochem 2003; 88: 57-75
• 25 Harada C, Harada T, Quah HM et al. Potential role of glial cell line-derived neurotrophic factor receptors in Muller glial cells during light-induced retinal degeneration. Neuroscience 2003; 122: 229-235
• 26 Zhang R, Zhang H, Xu L et al. Neuroprotective effect of intravitreal cell-based glucagon-like peptide-1 production in the optic nerve crush model. Acta Ophthalmol 2011; 89: e320-e326
• 27 Frasson M, Picaud S, Leveillard T et al. Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse. Invest Ophthalmol Vis Sci 1999; 40: 2724-2734
• 28 Hauck SM, Kinkl N, Deeg CA et al. GDNF family ligands trigger indirect neuroprotective signaling in retinal glial cells. Mol Cell Biol 2006; 26: 2746-2757
• 29 Hauck SM, Gloeckner CJ, Harley ME et al. Identification of paracrine neuroprotective candidate proteins by a functional assay-driven proteomics approach. Mol Cell Proteomics 2008; 7: 1349-1361
• 30 Bringmann A, Pannicke T, Grosche J et al. Muller cells in the healthy and diseased retina. Prog Retin Eye Res 2006; 25: 397-424
• 31 Franco R, Cidlowski JA. Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ 2009; 16: 1303-1314
• 32 Xu S, Touyz RM. Reactive oxygen species and vascular remodelling in hypertension: still alive. Can J Cardiol 2006; 22: 947-951
• 33 Usui S, Oveson BC, Lee SY et al. NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa. J Neurochem 2009; 110: 1028-1037
• 34 Paquet-Durand F, Silva J, Talukdar T et al. Excessive activation of poly(ADP-ribose) polymerase contributes to inherited photoreceptor degeneration in the retinal degeneration 1 mouse. J Neurosci 2007; 27: 10311-10319
• 35 Kaur J, Mencl S, Sahaboglu A et al. Calpain and PARP activation during photoreceptor cell death in P23H and S334ter rhodopsin mutant rats. PLoS One 2011; 6: e22181
• 36 Paquet-Durand F, Beck S, Michalakis S et al. A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa. Hum Mol Genet 2011; 20: 941-947
• 37 Sibulesky L, Hayes KC, Pronczuk A et al. Safety of < 7500 RE (< 25000 IU) vitamin A daily in adults with retinitis pigmentosa. Am J Clin Nutr 1999; 69: 656-663
• 38 Berson EL. Retinitis pigmentosa. The Friedenwald Lecture. Invest Ophthalmol Vis Sci 1993; 34: 1659-1676
• 39 Pasantes-Morales H, Quiroz H, Quesada O. Treatment with taurine, diltiazem, and vitamin E retards the progressive visual field reduction in retinitis pigmentosa: a 3-year follow-up study. Metab Brain Dis 2002; 17: 183-197
• 40 Derby H. On the possible retardation of retinitis pigmentosa. Trans Am Ophthalmol Soc 1886; 4: 217-227
• 41 Schatz A, Arango-Gonzalez B, Fischer D et al. Transcorneal electrical stimulation shows neuroprotective effects in retinas of light-exposed rats. Invest Ophthalmol Vis Sci 2012; 53: 5552-5561
• 42 Gekeler F. [Transcorneal electrostimulation]. Ophthalmologe 2012; 109: 129-135
• 43 Sancho-Pelluz J, Alavi MV, Sahaboglu A et al. Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse. Cell Death Dis 2010; 1: e24
• 44 Zhang R, Zhang H, Xu L et al. Intravitreal cell-based production of glucagon-like peptide-1. Retina 2011; 31: 785-789
• 45 Fischer MD, Goldmann T, Wallrapp C et al. Successful subretinal delivery and monitoring of MicroBeads in mice. PLoS One 2013; 8: e55173
• 46 Tansley K. The development of the rat eye in graft. J Exp Biol 1946; 22: 221-224
• 47 Steinberg RH. Interactions between the retinal pigment epithelium and the neural retina. Doc Ophthalmol 1985; 60: 327-346
• 48 Uygun BE, Sharma N, Yarmush M. Retinal pigment epithelium differentiation of stem cells: current status and challenges. Crit Rev Biomed Eng 2009; 37: 355-375
• 49 Radtke ND, Aramant RB, Petry HM et al. Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium. Am J Ophthalmol 2008; 146: 172-182
• 50 Pan CK, Heilweil G, Lanza R et al. Embryonic stem cells as a treatment for macular degeneration. Expert Opin Biol Ther 2013; 13: 1125-1133
• 51 Schwartz SD, Hubschman JP, Heilwell G et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet 2012; 379: 713-720
• 52 MacLaren RE, Bird AC, Sathia PJ et al. Long-term results of submacular surgery combined with macular translocation of the retinal pigment epithelium in neovascular age-related macular degeneration. Ophthalmology 2005; 112: 2081-2087
• 53 Gouras P, Du J, Gelanze M et al. Survival and synapse formation of transplanted rat rods. J Neural Transplant Plast 1991; 2: 91-100
• 54 Gouras P, Tanabe T. Survival and integration of neural retinal transplants in rd mice. Graefes Arch Clin Exp Ophthalmol 2003; 241: 403-409
• 55 Silverman MS, Hughes SE. Transplantation of photoreceptors to light-damaged retina. Invest Ophthalmol Vis Sci 1989; 30: 1684-1690
• 56 Kwan AS, Wang S, Lund RD. Photoreceptor layer reconstruction in a rodent model of retinal degeneration. Exp Neurol 1999; 159: 21-33
• 57 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
• 58 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
• 59 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
• 60 Dimos JT, Rodolfa KT, Niakan KK et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008; 321: 1218-1221
• 61 Park IH, Arora N, Huo H et al. Disease-specific induced pluripotent stem cells. Cell 2008; 134: 877-886
• 62 Osakada F, Ikeda H, Sasai Y et al. Stepwise differentiation of pluripotent stem cells into retinal cells. Nat Protoc 2009; 4: 811-824
• 63 Yu JY, Hu KJ, Smuga-Otto K et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009; 324: 797-801
• 64 Osakada F, Jin ZB, Hirami Y et al. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J Cell Sci 2009; 122: 3169-3179
• 65 Zrenner E. Will retinal implants restore vision?. Science 2002; 295: 1022-1025
• 66 Lagali PS, Balya D, Awatramani GB et al. Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci 2008; 11: 667-675