Zusammenfassung
In den vergangenen 10 Jahren wurden Strategien entwickelt, um hereditäre Dystrophien
und neovaskuläre Erkrankungen der Retina durch den Transfer von Genen zu behandeln.
Als optimale Genfähren (Vektoren) haben sich dabei rekombinante adenoassoziierte Viren
(rAAV) etabliert. Zur Behandlung retinaler Erkrankungen werden entweder Wildtyp-Kopien
der betroffenen Gene (spezifische Gentherapie) oder neuroprotektive bzw. antiangiogene
Faktoren (unspezifische Gentherapie) in der Retina exprimiert. Die erfolgreiche Behandlung
von RPE65–/–-Hunden (ein natürlich auftretendes Modell für bei Menschen auftretende Netzhautdystrophien)
durch spezifische Gentherapie wurde von verschiedenen Forschungsgruppen in den USA
und Europa gezeigt und basierend auf diesen Studien wurden mehrere klinische Studien
vorbereitet und begonnen. Um die Möglichkeit von unerwünschten Nebeneffekten durch
die Gentherapie in der Retina zu minimieren, muss die Expression von neuroprotektiven
bzw. antiangiogenen Faktoren regulierbar sein. Mehrere Regulationssysteme wurden schon
erfolgreich in der Retina von Großtiermodellen getestet und könnten demnächst in der
Klinik Anwendung finden.
Abstract
Over the last decade, significant progress has been made in the development of gene
therapy strategies for the treatment of neovascular disorders and inherited dystrophies
of the retina. Of all tested viral vectors, recombinant adeno-associated virus (rAAV)
vectors, have been shown to be optimal vectors for gene transfer to the retina. Broadly
speaking, two gene therapy strategies are used to treat retinal diseases; the first
being corrective expression in the retina of the mutated gene (i. e., specific gene
therapy) and the second being therapeutic expression of, for example, neurotrophic
or antiangiogenic factors, in cases of neurodegenerative or neovascular, respectively,
disorders (non-specific gene therapy). The naturally occurring RPE65–/– Briard dog model has been successfully treated by specific gene transfer protocols
and, based on these studies, the first clinical phase I trials are in preparation
or have already begun. To avoid potential negative side effects due to the expression
of neurotrophic and/or antiangiogenic factors in the retina, the expression of these
transgenes needs to be regulated into a therapeutic window. Several regulatory systems
have been tested in the retina of large animal models and may soon be used in clinical
applications.
Schlüsselwörter
Retina - Gentherapie - erbliche Netzhauterkrankungen - AAV - neovaskuläre Erkrankungen
der Retina - Regulationssysteme
Key words
retina - gene therapy - hereditary disorders of the retina - AAV - neovascular disorders
of the retina - regulatory systems
Literatur
- 1
Doonan F, Donovan M, Cotter T G.
Caspase-independent photoreceptor apoptosis in mouse models of retinal degeneration.
J Neurosci.
2003;
23 (13)
5723-5731
- 2
Marigo V.
Programmed cell death in retinal degeneration: targeting apoptosis in photoreceptors
as potential therapy for retinal degeneration.
Cell Cycle.
2007;
6 (6)
652-655
- 3
Wenzel A, Grimm C, Samardzija M. et al .
Molecular mechanisms of light-induced photoreceptor apoptosis and neuroprotection
for retinal degeneration.
Prog Retin Eye Res.
2005;
24 (2)
275-306
- 4
Holz F G, Pauleikhoff D, Klein R. et al .
Pathogenesis of lesions in late age-related macular disease.
Am J Ophthalmol.
2004;
137 (3)
504-510
- 5
Frank R N.
Diabetic retinopathy.
N Engl J Med.
2004;
350 (1)
48-58
- 6
Hartong D T, Berson E L, Dryja T P.
Retinitis pigmentosa.
Lancet.
2006;
368 (9549)
1795-1809
- 7
Rolling F.
Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives.
Gene Ther.
2004;
11 Suppl 1
S26-32
- 8
Auricchio A, Rolling F.
Adeno-associated viral vectors for retinal gene transfer and treatment of retinal
diseases.
Curr Gene Ther.
2005;
5 (3)
339-348
- 9
Warrington K H, Herzog R W.
Treatment of human disease by adeno-associated viral gene transfer.
Hum Genet.
2006;
119 (6)
571-603
- 10
Atchison R W, Casto B C, Hammon W M.
Adenovirus-Associated Defective Virus Particles.
Science.
1965;
149
754-756
- 11
Srivastava Jr A, Lusby E W, Berns K I.
Nucleotide sequence and organization of the adeno-associated virus 2 genome.
J Virol.
1983;
45 (2)
555-564
- 12
Flotte T R.
Gene therapy progress and prospects: recombinant adeno-associated virus (rAAV) vectors.
Gene Ther.
2004;
11 (10)
805-810
- 13
Gao G, Vandenberghe L H, Alvira M R. et al .
Clades of Adeno-associated viruses are widely disseminated in human tissues.
J Virol.
2004;
78 (12)
6381-6388
- 14
Mori S, Wang L, Takeuchi T. et al .
Two novel adeno-associated viruses from cynomolgus monkey: pseudotyping characterization
of capsid protein.
Virology.
2004;
330 (2)
375-383
- 15
Schmidt M, Grot E, Cervenka P. et al .
Identification and characterization of novel adeno-associated virus isolates in ATCC
virus stocks.
J Virol.
2006;
80 (10)
5082-5085
- 16
Samulski R J, Chang L S, Shenk T.
A recombinant plasmid from which an infectious adeno-associated virus genome can be
excised in vitro and its use to study viral replication.
J Virol.
1987;
61 (10)
3096-3101
- 17
Muzyczka N.
Use of adeno-associated virus as a general transduction vector for mammalian cells.
Curr Top Microbiol Immunol.
1992;
158
97-129
- 18
Rabinowitz J E, Rolling F, Li C. et al .
Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into
multiple AAV serotypes enables transduction with broad specificity.
J Virol.
2002;
76 (2)
791-801
- 19
Dudus L, Anand V, Acland G M. et al .
Persistent transgene product in retina, optic nerve and brain after intraocular injection
of rAAV.
Vision Res.
1999;
39 (15)
2545-2553
- 20
Guy J, Qi X, Muzyczka N. et al .
Reporter expression persists 1 year after adeno-associated virus-mediated gene transfer
to the optic nerve.
Arch Ophthalmol.
1999;
117 (7)
929-937
- 21
Folliot S, Briot D, Conrath H. et al .
Sustained tetracycline-regulated transgene expression in vivo in rat retinal ganglion
cells using a single type 2 adeno-associated viral vector.
J Gene Med.
2003;
5 (6)
493-501
- 22
Auricchio A, Kobinger G, Anand V. et al .
Exchange of surface proteins impacts on viral vector cellular specificity and transduction
characteristics: the retina as a model.
Hum Mol Genet.
2001;
10 (26)
3075-3081
- 23
Bennett J, Maguire A M, Cideciyan A V. et al .
Stable transgene expression in rod photoreceptors after recombinant adeno-associated
virus-mediated gene transfer to monkey retina.
Proc Natl Acad Sci U S A.
1999;
96 (17)
9920-9925
- 24
Le Meur G, Weber M, Pereon Y. et al .
Postsurgical assessment and long-term safety of recombinant adeno-associated virus-mediated
gene transfer into the retinas of dogs and primates.
Arch Ophthalmol.
2005;
123 (4)
500-506
- 25
Ali R R, Reichel M B, Thrasher A J. et al .
Gene transfer into the mouse retina mediated by an adeno-associated viral vector.
Hum Mol Genet.
1996;
5 (5)
591-594
- 26
Yang G S, Schmidt M, Yan Z. et al .
Virus-mediated transduction of murine retina with adeno-associated virus: effects
of viral capsid and genome size.
J Virol.
2002;
76 (15)
7651-7660
- 27
Bainbridge J W, Mistry A, Schlichtenbrede F C. et al .
Stable rAAV-mediated transduction of rod and cone photoreceptors in the canine retina.
Gene Ther.
2003;
10 (16)
1336-1344
- 28
Weber M, Rabinowitz J, Provost N. et al .
Recombinant adeno-associated virus serotype 4 mediates unique and exclusive long-term
transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after
subretinal delivery.
Mol Ther.
2003;
7 (6)
774-781
- 29
Lotery A J, Yang G S, Mullins R F. et al .
Adeno-associated virus type 5: transduction efficiency and cell-type specificity in
the primate retina.
Hum Gene Ther.
2003;
14 (17)
1663-1671
- 30
Natkunarajah M, Trittibach P, McIntosh J. et al .
Assessment of ocular transduction using single-stranded and self-complementary recombinant
adeno-associated virus serotype 2 / 8.
Gene Ther.
2008;
15 (6)
463-467
- 31
Allocca M, Mussolino C, Garcia-Hoyos M. et al .
Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors.
J Virol.
2007;
81 (20)
11 372-11 380
- 32
Stieger K, Colle M A, Dubreil L. et al .
Subretinal delivery of recombinant AAV serotype 8 vector in dogs results in gene transfer
to neurons in the brain.
Mol Ther.
2008;
15
epub March 11th
- 33
Bennett J, Duan D, Engelhardt J F. et al .
Real-time, noninvasive in vivo assessment of adeno-associated virus-mediated retinal
transduction.
Invest Ophthalmol Vis Sci.
1997;
38 (13)
2857-2863
- 34
Narfstrom K, Katz M L, Ford M. et al .
In vivo gene therapy in young and adult RPE65-/- dogs produces long-term visual improvement.
J Hered.
2003;
94 (1)
31-37
- 35
Acland G M, Aguirre G D, Ray J. et al .
Gene therapy restores vision in a canine model of childhood blindness.
Nat Genet.
2001;
28 (1)
92-95
- 36
Nicoletti A, Kawase K, Thompson D A.
Promoter analysis of RPE65, the gene encoding a 61-kDa retinal pigment epithelium-specific
protein.
Invest Ophthalmol Vis Sci.
1998;
39 (3)
637-644
- 37
Esumi N, Oshima Y, Li Y. et al .
Analysis of the VMD2 promoter and implication of E-box binding factors in its regulation.
J Biol Chem.
2004;
279 (18)
19 064-19 073
- 38
Lem J, Applebury M L, Falk J D. et al .
Tissue-specific and developmental regulation of rod opsin chimeric genes in transgenic
mice.
Neuron.
1991;
6 (2)
201-210
- 39
Zack D J, Bennett J, Wang Y. et al .
Unusual topography of bovine rhodopsin promoter-lacZ fusion gene expression in transgenic
mouse retinas.
Neuron.
1991;
6 (2)
187-199
- 40
Bennett J, Sun D, Kariko K.
Sequence analysis of the 5.34-kb 5’ flanking region of the human rhodopsin-encoding
gene.
Gene.
1995;
167 (1 – 2)
317-320
- 41
Chen J, Tucker C L, Woodford B. et al .
The human blue opsin promoter directs transgene expression in short-wave cones and
bipolar cells in the mouse retina.
Proc Natl Acad Sci U S A.
1994;
91 (7)
2611-2615
- 42
Fei Y.
Development of the cone photoreceptor mosaic in the mouse retina revealed by fluorescent
cones in transgenic mice.
Mol Vis.
2003;
9
31-42
- 43
Young J E, Vogt T, Gross K W. et al .
A short, highly active photoreceptor-specific enhancer/promoter region upstream of
the human rhodopsin kinase gene.
Invest Ophthalmol Vis Sci.
2003;
44 (9)
4076-4085
- 44
Kuzmanovic M, Dudley V J, Sarthy V P.
GFAP promoter drives Muller cell-specific expression in transgenic mice.
Invest Ophthalmol Vis Sci.
2003;
44 (8)
3606-3613
- 45
Jomary C, Vincent K A, Grist J. et al .
Rescue of photoreceptor function by AAV-mediated gene transfer in a mouse model of
inherited retinal degeneration.
Gene Ther.
1997;
4 (7)
683-690
- 46
Ali R R, Sarra G M, Stephens C. et al .
Restoration of photoreceptor ultrastructure and function in retinal degeneration slow
mice by gene therapy.
Nat Genet.
2000;
25 (3)
306-310
- 47
Schlichtenbrede F C, da Cruz L, Stephens C. et al .
Long-term evaluation of retinal function in Prph2Rd2 /Rd2 mice following AAV-mediated
gene replacement therapy.
J Gene Med.
2003;
5 (9)
757-764
- 48
Schlichtenbrede F C, Smith A J, Bainbridge J W. et al .
Improvement of neuronal visual responses in the superior colliculus in Prph2 (Rd2
/Rd2) mice following gene therapy.
Mol Cell Neurosci.
2004;
25 (1)
103-110
- 49
Sarra G M, Stephens C, Alwis de M. et al .
Gene replacement therapy in the retinal degeneration slow (rds) mouse: the effect
on retinal degeneration following partial transduction of the retina.
Hum Mol Genet.
2001;
10 (21)
2353-2361
- 50
Pawlyk B S, Smith A J, Buch P K. et al .
Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber
congenital amaurosis lacking RPGRIInvest.
Ophthalmol Vis Sci.
2005;
46 (9)
3039-3045
- 51
Haire S E, Pang J, Boye S L. et al .
Light-driven cone arrestin translocation in cones of postnatal guanylate cyclase-1
knockout mouse retina treated with AAV-GC1.
Invest Ophthalmol Vis Sci.
2006;
47 (9)
3745-3753
- 52
Zeng Y, Takada Y, Kjellstrom S. et al .
RS-1 Gene Delivery to an Adult Rs1h Knockout Mouse Model Restores ERG b-Wave with
Reversal of the Electronegative Waveform of X-Linked Retinoschisis.
Invest Ophthalmol Vis Sci.
2004;
45 (9)
3279-3285
- 53
Min S H, Molday L L, Seeliger M W. et al .
Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient
mouse model of x-linked juvenile retinoschisis.
Mol Ther.
2005;
12 (4)
644-651
- 54
Kjellstrom S, Bush R A, Zeng Y. et al .
Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: long-term rescue
from retinal degeneration.
Invest Ophthalmol Vis Sci.
2007;
48 (8)
3837-3845
- 55
Alexander J J, Umino Y, Everhart D. et al .
Restoration of cone vision in a mouse model of achromatopsia.
Nat Med.
2007;
13 (6)
685-687
- 56
Batten M L, Imanishi Y, Tu D C. et al .
Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse
model of Leber congenital amaurosis.
PLoS Med.
2005;
2 (11)
e333
- 57
Smith A J, Schlichtenbrede F C, Tschernutter M. et al .
AAV-Mediated gene transfer slows photoreceptor loss in the RCS rat model of retinitis
pigmentosa.
Mol Ther.
2003;
8 (2)
188-195
- 58
Narfstrom K, Katz M L, Bragadottir R. et al .
Functional and structural recovery of the retina after gene therapy in the RPE65 null
mutation dog.
Invest Ophthalmol Vis Sci.
2003;
44 (4)
1663-1672
- 59
Dejneka N S, Surace E M, Aleman T S. et al .
In utero gene therapy rescues vision in a murine model of congenital blindness.
Mol Ther.
2004;
9 (2)
182-188
- 60
Lai C M, Yu M J, Brankov M. et al .
Recombinant adeno-associated virus type 2-mediated gene delivery into the Rpe65-/-
knockout mouse eye results in limited rescue.
Genet Vaccines Ther.
2004;
2 (1)
3
- 61
Acland G M, Aguirre G D, 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 (6)
1072-1082
- 62
Pang J J, Chang B, Kumar A. et al .
Gene therapy restores vision-dependent behavior as well as retinal structure and function
in a mouse model of RPE65 Leber congenital amaurosis.
Mol Ther.
2006;
13 (3)
565-572
- 63
Le Meur G, Stieger K, Smith A J. et al .
Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector
that specifically targets the retinal pigmented epithelium.
Gene Ther.
2007;
14 (4)
292-303
- 64
Bennicelli J, Wright J F, Komaromy A. et al .
Reversal of Blindness in Animal Models of Leber Congenital Amaurosis Using Optimized
AAV2-mediated Gene Transfer.
Mol Ther.
2008;
22
22
- 65
Surace E M, Domenici L, Cortese K. et al .
Amelioration of both functional and morphological abnormalities in the retina of a
mouse model of ocular albinism following AAV-mediated gene transfer.
Mol Ther.
2005;
12 (4)
652-658
- 66
Moiseyev G, Chen Y, Takahashi Y. et al .
RPE65 is the isomerohydrolase in the retinoid visual cycle.
Proc Natl Acad Sci U S A.
2005;
102 (35)
12 413-12 418
- 67
Jin M, Li S, Moghrabi W N. et al .
Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium.
Cell.
2005;
122 (3)
449-459
- 68
Redmond T M, Yu S, Lee E. et al .
Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle.
Nat Genet.
1998;
20 (4)
344-351
- 69
Pang J J, Chang B, Hawes N L. et al .
Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human
Leber congenital amaurosis (LCA).
Mol Vis.
2005;
11
152-162
- 70
Aguirre G D, Baldwin V, Pearce-Kelling S. et al .
Congenital stationary night blindness in the dog: common mutation in the RPE65 gene
indicates founder effect.
Mol Vis.
1998;
4
23
- 71
Jacobson S G, Acland G M, Aguirre G D. et al .
Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular
subretinal injection.
Mol Ther.
2006;
13 (6)
1074-1084
- 72
Jacobson S G, Boye S L, Aleman T S. et al .
Safety in nonhuman primates of ocular AAV2-RPE65, a candidate treatment for blindness
in Leber congenital amaurosis.
Hum Gene Ther.
2006;
17 (8)
845-858
- 73
Dryja T P, Hahn L B, Cowley G S. et al .
Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis
pigmentosa.
Proc Natl Acad Sci U S A.
1991;
88 (20)
9370-9374
- 74
Lewin A S, Drenser K A, Hauswirth W W. et al .
Ribozyme rescue of photoreceptor cells in a transgenic rat model of autosomal dominant
retinitis pigmentosa.
Nat Med.
1998;
4 (8)
967-971
- 75
LaVail M M, Yasumura D, Matthes M T. et al .
Ribozyme rescue of photoreceptor cells in P 23 H transgenic rats: long-term survival
and late-stage therapy.
Proc Natl Acad Sci U S A.
2000;
97 (21)
11 488-11 493
- 76
Tessitore A, Parisi F, Denti M A. et al .
Preferential silencing of a common dominant rhodopsin mutation does not inhibit retinal
degeneration in a transgenic model.
Mol Ther.
2006;
14 (5)
692-699
- 77
Gorbatyuk M S, Pang J J, Thomas J. et al .
Knockdown of wild-type mouse rhodopsin using an AAV vectored ribozyme as part of an
RNA replacement approach.
Mol Vis.
2005;
11
648-656
- 78
Gorbatyuk M, Justilien V, Liu J. et al .
Preservation of photoreceptor morphology and function in P 23 H rats using an allele
independent ribozyme.
Exp Eye Res.
2007;
84 (1)
44-52
- 79
Gorbatyuk M, Justilien V, Liu J. et al .
Suppression of mouse rhodopsin expression in vivo by AAV mediated siRNA delivery.
Vision Res.
2007;
47 (9)
1202-1208
- 80
O’Reilly M, Millington-Ward S, Palfi A. et al .
A transgenic mouse model for gene therapy of rhodopsin-linked Retinitis Pigmentosa.
Vision Res.
2007;
5
5
- 81
O’Reilly M, Palfi A, Chadderton N. et al .
RNA interference-mediated suppression and replacement of human rhodopsin in vivo.
Am J Hum Genet.
2007;
81 (1)
127-135
- 82
Huang E J, Reichardt L F.
Trk receptors: roles in neuronal signal transduction.
Annu Rev Biochem.
2003;
72
609-642
- 83
Datta S R, Brunet A, Greenberg M E.
Cellular survival: a play in three Akts.
Genes Dev.
1999;
13 (22)
2905-2927
- 84
Lau D, McGee L H, Zhou S. et al .
Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2.
Invest Ophthalmol Vis Sci.
2000;
41 (11)
3622-3633
- 85
Green E S, Rendahl K G, Zhou S. et al .
Two animal models of retinal degeneration are rescued by recombinant adeno-associated
virus-mediated production of FGF-5 and FGF-18.
Mol Ther.
2001;
3 (4)
507-515
- 86
McGee Sanftner L H, Abel H, Hauswirth W W. et al .
Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a
transgenic rat model of retinitis pigmentosa.
Mol Ther.
2001;
4 (6)
622-629
- 87
Buch P K, MacLaren R E, Duran Y. et al .
In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances
gene replacement therapy in rodent models of retinal degeneration.
Mol Ther.
2006;
14 (5)
700-709
- 88
Allocca M, Di Vicino U, Petrillo M. et al .
Constitutive and AP 20 187-induced Ret activation in photoreceptors does not protect
from light-induced damage.
Invest Ophthalmol Vis Sci.
2007;
48 (11)
5199-5206
- 89
Peterson W M, Wang Q, Tzekova R. et al .
Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal
neurons and glia.
J Neurosci.
2000;
20 (11)
4081-4090
- 90
Beltran W A, Zhang Q, Kijas J W. et al .
Cloning, mapping, and retinal expression of the canine ciliary neurotrophic factor
receptor alpha (CNTFRalpha).
Invest Ophthalmol Vis Sci.
2003;
44 (8)
3642-3649
- 91
Liang F Q, Dejneka N S, Cohen D R. et al .
AAV-mediated delivery of ciliary neurotrophic factor prolongs photoreceptor survival
in the rhodopsin knockout mouse.
Mol Ther.
2001;
3 (2)
241-248
- 92
Liang F Q, Aleman T S, Dejneka N S. et al .
Long-term protection of retinal structure but not function using RAAV.CNTF in animal
models of retinitis pigmentosa.
Mol Ther.
2001;
4 (5)
461-472
- 93
Bok D, Yasumura D, Matthes M T. et al .
Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal
structure and function in mice with a P 216L rds/peripherin mutation.
Exp Eye Res.
2002;
74 (6)
719-735
- 94
Schlichtenbrede F C, MacNeil A, Bainbridge J W. et al .
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.
2003;
10 (6)
523-527
- 95
Wen R, Song Y, Kjellstrom S. et al .
Regulation of rod phototransduction machinery by ciliary neurotrophic factor.
J Neurosci.
2006;
26 (52)
13 523-13 530
- 96
Rhee K D, Ruiz A, Duncan J L. et al .
Molecular and cellular alterations induced by sustained expression of ciliary neurotrophic
factor in a mouse model of retinitis pigmentosa.
Invest Ophthalmol Vis Sci.
2007;
48 (3)
1389-1400
- 97
Grimm C, Wenzel A, Groszer M. et al .
HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced
retinal degeneration.
Nat Med.
2002;
8 (7)
718-724
- 98
Grimm C, Wenzel A, Stanescu D. et al .
Constitutive overexpression of human erythropoietin protects the mouse retina against
induced but not inherited retinal degeneration.
J Neurosci.
2004;
24 (25)
5651-5658
- 99
Grimm C, Hermann D M, Bogdanova A. et al .
Neuroprotection by hypoxic preconditioning: HIF-1 and erythropoietin protect from
retinal degeneration.
Semin Cell Dev Biol.
2005;
16 (4 – 5)
531-538
- 100
Grimm C, Wenzel A, Acar N. et al .
Hypoxic preconditioning and erythropoietin protect retinal neurons from degeneration.
Adv Exp Med Biol.
2006;
588
119-131
- 101
Rex T S, Allocca M, Domenici L. et al .
Systemic but not intraocular Epo gene transfer protects the retina from light-and
genetic-induced degeneration.
Mol Ther.
2004;
10 (5)
855-861
- 102
Sun M H, Pang J H, Chen S L. et al .
Photoreceptor protection against light damage by AAV-mediated overexpression of heme
oxygenase-1.
Invest Ophthalmol Vis Sci.
2007;
48 (12)
5699-5707
- 103
LaCasse E C, Baird S, Korneluk R G. et al .
The inhibitors of apoptosis (IAPs) and their emerging role in cancer.
Oncogene.
1998;
17 (25)
3247-3259
- 104
Deveraux Q L, Leo E, Stennicke H R. et al .
Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct
specificities for caspases.
Embo J.
1999;
18 (19)
5242-5251
- 105
Leonard K C, Petrin D, Coupland S G. et al .
XIAP Protection of Photoreceptors in Animal Models of Retinitis Pigmentosa.
PLoS ONE.
2007;
2
e314
- 106
Tomita H, Sugano E, Yawo H. et al .
Restoration of visual response in aged dystrophic RCS rats using AAV-mediated channelopsin-2
gene transfer.
Invest Ophthalmol Vis Sci.
2007;
48 (8)
3821-3826
- 107
Bi A, Cui J, Ma Y P. et al .
Ectopic expression of a microbial-type rhodopsin restores visual responses in mice
with photoreceptor degeneration.
Neuron.
2006;
50 (1)
23-33
- 108
Ng E W, Shima D T, Calias P. et al .
Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease.
Nat Rev Drug Discov.
2006;
5 (2)
123-132
- 109
Brown D M, Kaiser P K, Michels M. et al .
Ranibizumab versus verteporfin for neovascular age-related macular degeneration.
N Engl J Med.
2006;
355 (14)
1432-1444
- 110
Bashshur Z F, Bazarbachi A, Schakal A. et al .
Intravitreal bevacizumab for the management of choroidal neovascularization in age-related
macular degeneration.
Am J Ophthalmol.
2006;
142 (1)
1-9
- 111
Ferrara N, Kerbel R S.
Angiogenesis as a therapeutic target.
Nature.
2005;
438 (7070)
967-974
- 112
Jager R D, Aiello L P, Patel S C. et al .
Risks of intravitreous injection: a comprehensive review.
Retina.
2004;
24 (5)
676-698
- 113
Ryan S J.
Subretinal neovascularization. Natural history of an experimental model.
Arch Ophthalmol.
1982;
100 (11)
1804-1809
- 114
Mori K, Gehlbach P, Yamamoto S. et al .
AAV-mediated gene transfer of pigment epithelium-derived factor inhibits choroidal
neovascularization.
Invest Ophthalmol Vis Sci.
2002;
43 (6)
1994-2000
- 115
Lai C C, Wu W C, Chen S L. et al .
Suppression of choroidal neovascularization by adeno-associated virus vector expressing
angiostatin.
Invest Ophthalmol Vis Sci.
2001;
42 (10)
2401-2407
- 116
Lai Y K, Shen W Y, Brankov M. et al .
Potential long-term inhibition of ocular neovascularisation by recombinant adeno-associated
virus-mediated secretion gene therapy.
Gene Ther.
2002;
9 (12)
804-813
- 117
Lai C M, Shen W Y, Brankov M. et al .
Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization
in mice and monkeys.
Mol Ther.
2005;
12 (4)
659-668
- 118
Smith L E, Wesolowski E, McLellan A. et al .
Oxygen-induced retinopathy in the mouse.
Invest Ophthalmol Vis Sci.
1994;
35 (1)
101-111
- 119
Okamoto N, Tobe T, Hackett S F. et al .
Transgenic mice with increased expression of vascular endothelial growth factor in
the retina: a new model of intraretinal and subretinal neovascularization.
Am J Pathol.
1997;
151 (1)
281-291
- 120
Lai C M, Dunlop S A, May L A. et al .
Generation of transgenic mice with mild and severe retinal neovascularisation.
Br J Ophthalmol.
2005;
89 (7)
911-916
- 121
Ruberte J, Ayuso E, Navarro M. et al .
Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease.
J Clin Invest.
2004;
113 (8)
1149-1157
- 122
Yamada H, Yamada E, Higuchi A. et al .
Retinal neovascularisation without ischaemia in the spontaneously diabetic Torii rat.
Diabetologia.
2005;
48 (8)
1663-1668
- 123
Raisler B J, Berns K I, Grant M B. et al .
Adeno-associated virus type-2 expression of pigmented epithelium-derived factor or
Kringles 1 – 3 of angiostatin reduce retinal neovascularization.
Proc Natl Acad Sci U S A.
2002;
99 (13)
8909-8914
- 124
Auricchio A, Behling K C, Maguire A M. et al .
Inhibition of retinal neovascularization by intraocular viral-mediated delivery of
anti-angiogenic agents.
Mol Ther.
2002;
6 (4)
490-494
- 125
Deng W T, Yan Z, Dinculescu A. et al .
Adeno-associated virus-mediated expression of vascular endothelial growth factor peptides
inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy.
Hum Gene Ther.
2005;
16 (11)
1247-1254
- 126
Bainbridge J W, Mistry A, De Alwis M. et al .
Inhibition of retinal neovascularisation by gene transfer of soluble VEGF receptor
sFlt-1.
Gene Ther.
2002;
9 (5)
320-326
- 127
Ideno J, Mizukami H, Kakehashi A. et al .
Prevention of diabetic retinopathy by intraocular soluble flt-1 gene transfer in a
spontaneously diabetic rat model.
Int J Mol Med.
2007;
19 (1)
75-79
- 128
Alon T, Hemo I, Itin A. et al .
Vascular endothelial growth factor acts as a survival factor for newly formed retinal
vessels and has implications for retinopathy of prematurity.
Nat Med.
1995;
1 (10)
1024-1028
- 129
Oosthuyse B, Moons L, Storkebaum E. et al .
Deletion of the hypoxia-response element in the vascular endothelial growth factor
promoter causes motor neuron degeneration.
Nat Genet.
2001;
28 (2)
131-138
- 130
Baffert F, Le T, Sennino B. et al .
Cellular changes in normal blood capillaries undergoing regression after inhibition
of VEGF signaling.
Am J Physiol Heart Circ Physiol.
2006;
290 (2)
H547-559
- 131
Gossen M, Bujard H.
Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
Proc Natl Acad Sci USA.
1992;
89 (12)
5547-5551
- 132
Rivera V M, Clackson T, Natesan S. et al .
A humanized system for pharmacologic control of gene expression.
Nat Med.
1996;
2 (9)
1028-1032
- 133
Boast K, Binley K, Iqball S. et al .
Characterization of physiologically regulated vectors for the treatment of ischemic
disease.
Hum Gene Ther.
1999;
10 (13)
2197-2208
- 134
Gossen M, Freundlieb S, Bender G. et al .
Transcriptional activation by tetracyclines in mammalian cells.
Science.
1995;
268 (5218)
1766-1769
- 135
McGee Sanftner L H, Rendahl K G, Quiroz D. et al .
Recombinant AAV-mediated delivery of a tet-inducible reporter gene to the rat retina.
Mol Ther.
2001;
3 (5 Pt 1)
688-696
- 136
Smith J R, Verwaerde C, Rolling F. et al .
Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated
virus in experimental autoimmune uveoretinitis.
Hum Gene Ther.
2005;
16 (9)
1037-1046
- 137
Stieger K, Le Meur G, Lasne F. et al .
Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates
following subretinal injection of recombinant AAV vectors.
Mol Ther.
2006;
13 (5)
967-975
- 138
Stieger K, Mendes-Madeira A, Meur G L. et al .
Oral administration of doxycycline allows tight control of transgene expression: a
key step towards gene therapy of retinal diseases.
Gene Ther.
2007;
14 (23)
1668-1673
- 139
Le Guiner C, Stieger K, Snyder R O. et al .
Immune responses to gene product of inducible promoters.
Curr Gene Ther.
2007;
7 (5)
334-346
- 140
Auricchio A, Rivera V M, Clackson T. et al .
Pharmacological regulation of protein expression from adeno-associated viral vectors
in the eye.
Mol Ther.
2002;
6 (2)
238-242
- 141
Lebherz C, Auricchio A, Maguire A M. et al .
Long-term inducible gene expression in the eye via adeno-associated virus gene transfer
in nonhuman primates.
Hum Gene Ther.
2005;
16 (2)
178-186
- 142
Rivera V M, Gao G P, Grant R L. et al .
Long-term pharmacologically regulated expression of erythropoietin in primates following
AAV-mediated gene transfer.
Blood.
2005;
105 (4)
1424-1430
- 143
Bainbridge J W, Mistry A, Binley K. et al .
Hypoxia-regulated transgene expression in experimental retinal and choroidal neovascularization.
Gene Ther.
2003;
10 (12)
1049-1054
- 144
MacLaren R E, Pearson R A, MacNeil A. et al .
Retinal repair by transplantation of photoreceptor precursors.
Nature.
2006;
444 (7116)
203-207
- 145
Andrieu-Soler C, Halhal M, Boatright J H. et al .
Single-stranded oligonucleotide-mediated in vivo gene repair in the rd1 retina.
Mol Vis.
2007;
13
692-706
Dr. Knut Stieger
Klinik und Poliklinik für Augenheilkunde, Justus-Liebig-Universität Gießen
Friedrichstr. 18
35385 Gießen
Phone: ++ 49/6 41/9 94 38 35
Fax: ++ 49/6 41/99 4 39 99
Email: knut.stieger@uniklinikum-giessen.de
