Zusammenfassung
In genetisch bedingten Netzhautdystrophien sterben die Photorezeptoren durch Apoptose. Dies ist ein Prozess, dem komplexe molekulare Abläufe zugrunde liegen und der iniziiert wird, wenn proapoptotische Signale in der individuellen Zelle die Oberhand gewinnen. Die Identifizierung der beteiligten Faktoren und deren Wirkungen schuf die Basis dafür, diejenigen mit antiapoptotischem Potenzial in Tiermodellen für vererbte Netzhautdegenerationen auszutesten. Etliche dieser Faktoren waren in der Lage, den Gang der Degeneration zu verlangsamen. Ein Aufhalten oder gar ein Verhindern des Krankheitsverlaufs ist jedoch bis dato nicht realisiert. Zudem zeigte sich, dass der Erhalt der Morphologie nicht mit dem Erhalt der Funktion im ERG korrelieren muss. Vertiefte Einsichten in die pro- und antiapoptotischen Netzwerke sind klar vonnöten, damit antiapoptotische Therapien mit Überlebensfaktoren den Weg zur Applikation beim Menschen finden. Im Vergleich dazu konnte in einem Hundemodell für Leber-Amaurose durch elektive Gentherapie die retinale Funktion hergestellt und somit der Nachweis der Wirksamkeit der Methode erbracht werden.
Abstract
Hereditary retinal degeneration is characterized by apoptotic photoreceptor loss, a process governed by intricate molecular interplay and initiated when proapoptotic signals predominate in the individual cell. Identification of molecules involved and their actions has paved the way for testing the ones with antiapoptotic functions in models of inherited retinal degeneration. Many of these factors are able to slow the course of the degeneration. However, to date no such treatment has been able to stop or even prevent the devolution of the disorder. Moreover, preservation of morphology does not necessarily correlate with preservation of ERG function. Deepened understanding of the pro- and antiapoptotic networks is clearly needed for survival factors to be feasible for therapy in humans. In comparison, in a dog model of Leber’s congenital amaurosis gene therapy could establish retinal function, thus supplying proof of efficacy of the method.
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Literatur
Ahuja P et al. (2001) Lens epithelium-derived growth factor (LEDGF) delays photoreceptor degeneration in explants of rd/rd mouse retina. Neuroreport 12(13):2951–2955
Akimoto M et al. (1999) Adenovirally expressed basic fibroblast growth factor rescues photoreceptor cells in RCS rats. Invest Ophthalmol Vis Sci 40(2):273–279
Cao W et al. (2001) In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 42(7):1646–1652
Casson RJ et al. (2003) The effect of ischemic preconditioning on light-induced photoreceptor injury. Invest Ophthalmol Vis Sci 44(3):1348–1354
Casson RJ et al. (2004) The effect of retinal ganglion cell injury on light-induced photoreceptor degeneration. Invest Ophthalmol Vis Sci 45(2):685–693
Cayouette M et al. (1999) Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations. Neurobiol Dis 6(6):523–532
Chaum E (2003) Retinal neuroprotection by growth factors: a mechanistic perspective. J Cell Biochem 88(1):57–75
Chong NH et al. (1999) Repeated injections of a ciliary neurotrophic factor analogue leading to long-term photoreceptor survival in hereditary retinal degeneration. Invest Ophthalmol Vis Sci 40(6):1298–1305
Gassmann M et al. (2003) Non-erythroid functions of erythropoietin. Adv Exp Med Biol 543:323–330
Green ES et al. (2001) Two animal models of retinal degeneration are rescued by recombinant adeno-associated virus-mediated production of FGF-5 and FGF-18. Mol Ther 3(4):507–515
Grimm C et al. (2002) HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8(7):718–724
Grimm C et al. (2004) Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration. J Neurosci 24(25):5651–5658
Harada T et al. (2000) Modification of glial-neuronal cell interactions prevents photoreceptor apoptosis during light-induced retinal degeneration. Neuron 26(2):533–541
Ip NY et al. (1992) CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell 69(7):1121–1132
Kano T et al. (2002) Protective effect against ischemia and light damage of iris pigment epithelial cells transfected with the BDNF gene. Invest Ophthalmol Vis Sci 43(12):3744–375̄3
Lambiase A, Aloe L (1996) Nerve growth factor delays retinal degeneration in C3H mice. Graefes Arch Clin Exp Ophthalmol 234(Suppl 1):S96–100
Lau D et al. (2000) Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2. Invest Ophthalmol Vis Sci 41(11):3622–3633
Lau D, Flannery J (2003) Viral-mediated FGF-2 treatment of the constant light damage model of photoreceptor degeneration. Doc Ophthalmol 106(1):89–98
LaVail MM et al. (1998) Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci 39(3):592–602
Lawrence JM et al. (2004) Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons rats. Invest Ophthalmol Vis Sci 45(1):267–274
Lenzi L et al. (2005) Effect of exogenous administration of nerve growth factor in the retina of rats with inherited retinitis pigmentosa. Vision Res 45(12):1491–1500
Leveillard T et al. (2004) Identification and characterization of rod-derived cone viability factor. Nat Genet 36:755–759
Li F, Cao W Anderson RE (2003) Alleviation of constant-light-induced photoreceptor degeneration by adaptation of adult albino rat to bright cyclic light. Invest Ophthalmol Vis Sci 44(11):4968–4975
Liang FQ et al. (2001) AAV-mediated delivery of ciliary neurotrophic factor prolongs photoreceptor survival in the rhodopsin knockout mouse. Mol Ther 3(2):241–248
Liang FQ et al. (2001) Long-term protection of retinal structure but not function using RAAV.CNTF in animal models of retinitis pigmentosa. Mol Ther 4(5):461–472
Liang FQ et al. (2001) Melatonin delays photoreceptor degeneration in the rds/rds mouse. Neuroreport 12(5):1011–1014
Liu C et al. (1998) Preconditioning with bright light evokes a protective response against light damage in the rat retina. J Neurosci 18(4):1337–1344
Machida S et al. (2001) Lens epithelium-derived growth factor promotes photoreceptor survival in light-damaged and RCS rats. Invest Ophthalmol Vis Sci 42(5):1087–1095
Machida S et al. (2004) Neuroprotective effect of hepatocyte growth factor against photoreceptor degeneration in rats. Invest Ophthalmol Vis Sci 45(11):4174–4182
Miyazaki M et al. (2003) Simian lentiviral vector-mediated retinal gene transfer of pigment epithelium-derived factor protects retinal degeneration and electrical defect in Royal College of Surgeons rats. Gene Ther 10(17):1503–1511
Neuner-Jehle M et al. (2000) Ocular cell transfection with the human basic fibroblast growth factor gene delays photoreceptor cell degeneration in RCS rats. Hum Gene Ther 11(13):1875–1890
Okoye G et al. (2003) Increased expression of brain-derived neurotrophic factor preserves retinal function and slows cell death from rhodopsin mutation or oxidative damage. J Neurosci 23(10):4164–4172
Pennica D et al. (1996) Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons. Neuron 17(1):63–74
Rex TS et al. (2004) Systemic but not intraocular Epo gene transfer protects the retina from light- and genetic-induced degeneration. Mol Ther 10(5):855–861
Schlichtenbrede FC et al. (2003) Intraocular gene delivery of ciliary neurotrophic factor results in significant loss of retinal function in normal mice and in the Prph2Rd2/Rd2 model of retinal degeneration. Gene Ther 10(6):523–527
Sheng Z et al. (1997) Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem 272(9):5783–5791
Shibuki H et al. (2002) Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemia-reperfusion injury. Invest Ophthalmol Vis Sci 43(2):528–536
Shinohara,T, Singh DP Fatma N (2002) LEDGF, a survival factor, activates stress-related genes. Prog Retin Eye Res 21(3):341–358
Song Y et al. (2003) Photoreceptor protection by cardiotrophin-1 in transgenic rats with the rhodopsin mutation s334ter. Invest Ophthalmol Vis Sci 44(9):4069–4075
Spencer B et al. (2001) HSV-1 vector-delivered FGF2 to the retina is neuroprotective but does not preserve functional responses. Mol Ther 3(5):746–756
Sugawara T et al. (1998) The melatonin antagonist luzindole protects retinal photoreceptors from light damage in the rat. Invest Ophthalmol Vis Sci 39(12):2458–2465
Tao W et al. (2002) Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci 43(10):3292–3298
Tombran-Tink J, Barnstable CJ (2003) PEDF: a multifaceted neurotrophic factor. Nat Rev Neurosci 4(8):628–636
Uteza Y et al. (1999) Intravitreous transplantation of encapsulated fibroblasts secreting the human fibroblast growth factor 2 delays photoreceptor cell degeneration in Royal College of Surgeons rats. Proc Natl Acad Sci U S A 96(6):3126–3131
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Frigg, R., Wenzel, A., Grimm, C. et al. Überlebensfaktoren in der Therapie erblicher Netzhautdegenerationen. Ophthalmologe 102, 757–763 (2005). https://doi.org/10.1007/s00347-005-1244-0
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DOI: https://doi.org/10.1007/s00347-005-1244-0