Spontaneous canine models exist for several inherited retinal dystrophies. This review will summarize the models and indicate where they have been used in translational gene therapy trials. The RPE65 gene therapy trials to treat childhood blindness are a good example of how studies in dogs have contributed to therapy development. Outcomes in human clinical trials are compared and contrasted with the result of the preclinical dog trials.
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References
1.
MowatFM, Petersen-JonesSM, WilliamsonH, et al.Topographical characterization of cone photoreceptors and the area centralis of the canine retina. Mol Vis, 2008; 14:2518–2527.
2.
BeltranWA, CideciyanAV, GuziewiczKE, et al.Canine retina has a primate fovea-like bouquet of cone photoreceptors which is affected by inherited macular degenerations. PLoS One, 2014; 9:e90390.
3.
KoenekoopRK. An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol, 2004; 49:379–398.
4.
StoneEM. Leber congenital amaurosis—a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol, 2007; 144:791–811.
5.
Den HollanderAI, RoepmanR, KoenekoopRK, et al.Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res, 2008; 27:391–419.
6.
JinM, LiS, MoghrabiWN, et al.Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell, 2005; 122:449–459.
7.
RedmondTM, PoliakovE, YuS, et al.Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci USA, 2005; 102:13658–13663.
8.
WangJS, EstevezME, CornwallMC, et al.Intra-retinal visual cycle required for rapid and complete cone dark adaptation. Nat Neurosci, 2009; 12:295–302.
9.
JacobsonSG, AlemanTS, CideciyanAV, et al.Human cone photoreceptor dependence on RPE65 isomerase. Proc Natl Acad Sci USA, 2007; 104:15123–15128.
10.
CideciyanAV. Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res, 2010; 29:398–427.
11.
NarfstromK, WrigstadA, NilssonSE. The briard dog: a new animal model of congenital stationary night blindness. Br J Ophthalmol, 1989; 73:750–756.
12.
WrigstadA, NilssonSE, NarfströmK. Ultrastructural changes of the retina and the retinal pigment epithelium in briard dogs with hereditary congenital night blindness and partial day blindness. Exp Eye Res, 1992; 55:805–818.
13.
WrigstadA, NarfströmK, NilssonSE. Slowly progressive changes of the retina and retinal pigment epithelium in briard dogs with hereditary retinal dystrophy. A morphological study. Doc Ophthalmol, 1994; 87:337–354.
14.
VeskeA, NilssonSE, NarfströmK, et al.Retinal dystrophy of Swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics, 1999; 57:57–61.
15.
AguirreGD, BaldwinV, Pearce-KellingS, et al.Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect. Mol Vis, 1998; 4:23.
16.
AclandGM, AguirreGD, RayJ, et al.Gene therapy restores vision in a canine model of childhood blindness. Nat Genet, 2001; 28:92–95.
17.
AclandGM, AguirreGD, BennettJ, 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.
18.
AguirreGK, KomaromyAM, CideciyanAV, et al.Canine and human visual cortex intact and responsive despite early retinal blindness from RPE65 mutation. PLoS Med, 2007; 4:e230.
19.
JacobsonSG, AclandGM, AguirreGD, et al.Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol Ther, 2006; 13:1074–1084.
20.
NarfstromK, KatzML, BragadottirR, et al.Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog. Invest Ophthalmol Vis Sci, 2003; 44:1663–1672.
21.
NarfströmK, KatzML, FordM, et al.In vivo gene therapy in young and adult RPE65-/- dogs produces long-term visual improvement. J Hered, 2003; 94:31–37.
22.
FordM, BragadottirR, RakoczyPE, et al.Gene transfer in the RPE65 null mutation dog: relationship between construct volume, visual behavior and electroretinographic (ERG) results. Doc Ophthalmol, 2003; 107:79–86.
23.
Le MeurG, StiegerK, SmithAJ, 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; 14:292–303.
24.
JacobsJB, Dell'ossoLF, HertleRW, et al.Eye movement recordings as an effectiveness indicator of gene therapy in RPE65-deficient canines: implications for the ocular motor system. Invest Ophthalmol Vis Sci, 2006; 47:2865–2875.
25.
DejnekaNS, SuraceEM, AlemanTS, et al.In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther, 2004; 9:182–188.
26.
PangJJ, ChangB, KumarA, 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; 13:565–572.
27.
LaiCM, YuMJ, BrankovM, 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; 2:3.
28.
BainbridgeJW, SmithAJ, BarkerSS, et al.Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med, 2008; 358:2231–2239.
29.
MaguireAM, SimonelliF, PierceEA, et al.Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med, 2008; 358:2240–2248.
30.
HauswirthWW, AlemanTS, KaushalS, et al.Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther, 2008; 19:979–990.
31.
BaninE, Bandah-RozenfeldD, ObolenskyA, et al.Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel. Hum Gene Ther, 2010; 21:1749–1757.
32.
SimonelliF, MaguireAM, TestaF, et al.Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther, 2010; 18:643–650.
33.
CideciyanAV, HauswirthWW, AlemanTS, et al.Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther, 2009; 20:999–1004.
34.
JacobsonSG, CideciyanAV, RatnakaramR, et al.Gene therapy for Leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years. Arch Ophthalmol, 2012; 130:9–24.
35.
MaguireAM, HighKA, AuricchioA, et al.Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet, 2009; 374:1597–1605.
36.
AshtariM, CyckowskiLL, MonroeJF, et al.The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest, 2011; 121:2160–2168.
37.
BennettJ, AshtariM, WellmanJ, et al.AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med, 2012; 4:120ra15.
38.
TestaF, MaguireAM, RossiS, et al.Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital amaurosis type 2. Ophthalmology, 2013; 120:1283–1291.
39.
MelilloP, PecchiaL, TestaF, et al.Pupillometric analysis for assessment of gene therapy in Leber congenital amaurosis patients. Biomed Eng Online, 2012; 11:40.
40.
CideciyanAV, AlemanTS, BoyeSL, et al.Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA, 2008; 105:15112–15117.
41.
CideciyanAV, JacobsonSG, BeltranWA, et al.Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. Proc Natl Acad Sci USA, 2013; 110:E517–E525.
42.
CideciyanAV, HauswirthWW, AlemanTS, et al.Vision 1 year after gene therapy for Leber's congenital amaurosis. N Engl J Med, 2009; 361:725–727.
43.
AnnearMJ, MowatFM, BartoeJT, et al.Successful gene therapy in older Rpe65-deficient dogs following subretinal injection of an adeno-associated vector expressing RPE65. Hum Gene Ther, 2013; 24:883–893.
44.
MowatF, OccelliL, GervaisK, et al.Rapid photoreceptor degeneration in the area centralis and visual streak of Rpe65-deficient dogs: morphologic and histologic characterization. ARVO Meet Abstr, 2013; 54:1776.
45.
MowatFM, BreuwerAR, BartoeJT, et al.RPE65 gene therapy slows cone loss in Rpe65-deficient dogs. Gene Ther, 2013; 20:545–555.
46.
AmadoD, MingozziF, HuiD, et al.Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med, 2010; 2:21ra16.
47.
AnnearMJ, BartoeJT, BarkerSE, et al.Gene therapy in the second eye of RPE65-deficient dogs improves retinal function. Gene Ther, 2011; 18:53–61.
AguirreGD, RubinLF. Rod–cone dysplasia (progressive retinal atrophy) in Irish setters. J Am Vet Med Assoc, 1975; 166:157–164.
51.
TuntivanichN, PittlerSJ, FischerAJ, et al.Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6a mutation. Invest Ophthalmol Vis Sci, 2009; 50:801–813.
52.
SuberML, PittlerSJ, QuinN, et al.Irish setter dogs affected with rod–cone dysplasia contain a nonsense mutation in the rod cGMP phosphodiesterase beta-subunit gene. Proc Natl Acad Sci USA, 1993; 90:3968–3972.
53.
Petersen-JonesSM, EntzDD, SarganDR. cGMP phosphodiesterase-α mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog. Invest Ophthalmol Vis Sci, 1999; 40:1637–1644.
54.
PetitL, LheriteauE, WeberM, et al.Restoration of vision in the pde6beta-deficient dog, a large animal model of rod–cone dystrophy. Mol Ther, 2012; 20:2019–2030.
55.
GaubBM, BerryMH, HoltAE, et al.Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells. Proc Natl Acad Sci USA, 2014; 111:E5574–E5583.
56.
MowatFM, BartoeJT, BruewerA, et al.Evaluation of rod photoreceptor function and preservation following retinal gene therapy in the PDE6a mutant dog. ARVO Meet Abstr, 2012; 53:1928.
57.
KijasJW, CideciyanAV, AlemanTS, et al.Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc Natl Acad Sci USA, 2002; 99:6328–6333.
58.
CideciyanAV, JacobsonSG, AlemanTS, et al.In vivo dynamics of retinal injury and repair in the rhodopsin mutant dog model of human retinitis pigmentosa. Proc Natl Acad Sci USA, 2005; 102:5233–5238.
59.
ZhuL, JangGF, JastrzebskaB, et al.A naturally occurring mutation of the opsin gene (T4R) in dogs affects glycosylation and stability of the G protein-coupled receptor. J Biol Chem, 2004; 279:53828–53839.
60.
KomaromyAM, AclandGM, AguirreGD. Operating in the dark: a night-vision system for surgery in retinas susceptible to light damage. Arch Ophthalmol, 2008; 126:714–717.
61.
IwabeS, GeniniS, SudharsanR, et al.Assessment of AAV-mediated RHO augmentation in the canine T4R RHO model of autosomal dominant retinitis pigmentosa. Invest Ophthalmol Vis Sci, 2014; 55:3316.
62.
GorbatyukMS, AguirreGD, AclandGM, et al.Molecular therapeutic approaches for treatment of autosomal dominant RP (ADRP) in a canine T4R rhodopsin model. Invest Ophthalmol Vis Sci, 2003; 44:2341.
63.
WrightRN, HongDH, PerkinsB. Misexpression of the constitutive Rpgr(ex1-19) variant leads to severe photoreceptor degeneration. Invest Ophthalmol Vis Sci, 2011; 52:5189–5201.
64.
ZeissCJ, AclandGM, AguirreGD. Retinal pathology of canine X-linked progressive retinal atrophy, the locus homologue of RP3. Invest Ophthalmol Vis Sci, 1999; 40:3292–3304.
65.
ZhangQ, AclandGM, WuWX, et al.Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum Mol Genet, 2002; 11:993–1003.
66.
BeltranWA, CideciyanAV, LewinAS, et al.Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa. Proc Natl Acad Sci USA, 2012; 109:2132–2137.
67.
BeltranWA, CideciyanAV, LewinAS, et al.Gene augmentation for X-linked retinitis pigmentosa caused by mutations in RPGR. Cold Spring Harb Perspect Med, 2014; pii:a017392.
68.
BeltranWA, CideciyanAV, LewinAS, et al.RPGR gene augmentation delivered at early, mid and late stage disease in a canine model of XLRP rescues photoreceptor structure and function. Invest Ophthalmol Vis Sci, 2014; 55:3321.
69.
MellershCS, BoursnellME, PettittL, et al.Canine RPGRIP1 mutation establishes cone–rod dystrophy in miniature longhaired dachshunds as a homologue of human Leber congenital amaurosis. Genomics, 2006; 88:293–301.
70.
MiyaderaK, KatoK, Aguirre-HernandezJ, et al.Phenotypic variation and genotype-phenotype discordance in canine cone–rod dystrophy with an RPGRIP1 mutation. Mol Vis, 2009; 15:2287–2305.
71.
KuznetsovaT, IwabeS, Boesze-BattagliaK, et al.Exclusion of RPGRIP1 ins44 from primary causal association with early-onset cone–rod dystrophy in dogs. Invest Ophthalmol Vis Sci, 2012; 53:5486–5501.
72.
MiyaderaK, KatoK, BoursnellM, et al.Genome-wide association study in RPGRIP1(-/-) dogs identifies a modifier locus that determines the onset of retinal degeneration. Mamm Genome, 2012; 23:212–223.
73.
KuznetsovaT, ZangerlB, GoldsteinO, et al.Structural organization and expression pattern of the canine RPGRIP1 isoforms in retinal tissue. Invest Ophthalmol Vis Sci, 2011; 52:2989–2998.
74.
LheriteauE, PetitL, WeberM, et al.Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone–rod dystrophy. Mol Ther, 2014; 22:265–277.
75.
TurneyC, ChongNH, AlexanderRA, et al.Pathological and electrophysiological features of a canine cone–rod dystrophy in the miniature longhaired dachshund. Invest Ophthalmol Vis Sci, 2007; 48:4240–4249.
SidjaninDJ, LoweJK, McelweeJL, et al.Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum Mol Genet, 2002; 11:1823–1833.
78.
YehCY, GoldsteinO, KukekovaAV, et al.Genomic deletion of CNGB3 is identical by descent in multiple canine breeds and causes achromatopsia. BMC Genet, 2013; 14:27.
79.
KomaromyAM, RowlanJS, CorrAT, et al.Transient photoreceptor deconstruction by CNTF enhances rAAV-mediated cone functional rescue in late stage CNGB3-achromatopsia. Mol Ther, 2013; 21:1131–1141.
80.
KomaromyAM, AlexanderJJ, CooperAE, et al.Targeting gene expression to cones with human cone opsin promoters in recombinant AAV. Gene Ther, 2008; 15:1049–1055.
81.
KomaromyAM, AlexanderJJ, RowlanJS, et al.Gene therapy rescues cone function in congenital achromatopsia. Hum Mol Genet, 2010; 19:2581–2593.
82.
GarciaMM, YingGS, CocoresCA, et al.Evaluation of a behavioral method for objective vision testing and identification of achromatopsia in dogs. Am J Vet Res, 2010; 71:97–102.
83.
CarvalhoLS, XuJ, PearsonRA, et al.Long-term and age-dependent restoration of visual function in a mouse model of CNGB3-associated achromatopsia following gene therapy. Hum Mol Genet, 2011; 20:3161–3175.
84.
TaoW, WenR, GoddardMB, et al.Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci, 2002; 43:3292–3298.
85.
SievingPA, CarusoRC, TaoW, et al.Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA, 2006; 103:3896–3901.
86.
WenR, SongY, KjellstromS, et al.Regulation of rod phototransduction machinery by ciliary neurotrophic factor. J Neurosci, 2006; 26:13523–13530.
87.
BaninE, ObolenskyA, EjzenbergA, et al.Gene therapy in a sheep model of CNGA3 achromatopsia. Invest Ophthalmol Vis Sci, 2014; 55:4566.
88.
ZoborD, StanzialF, KellnerU, et al.Retinal structure and function in achromatopsia: the CNGA3 phenotype. Invest Ophthalmol Vis Sci, 2014; 55:346.
89.
GuziewiczKE, ZangerlB, LindauerSJ, et al.Bestrophin gene mutations cause canine multifocal retinopathy: a novel animal model for best disease. Invest Ophthalmol Vis Sci, 2007; 48:1959–1967.
90.
ZangerlB, WickstromK, SlavikJ, et al.Assessment of canine BEST1 variations identifies new mutations and establishes an independent bestrophinopathy model (cmr3). Mol Vis, 2010; 16:2791–2804.
91.
GuziewiczKE, ZangerlB, KomaromyAM, et al.Recombinant AAV-mediated BEST1 transfer to the retinal pigment epithelium: analysis of serotype-dependent retinal effects. PLoS One, 2013; 8:e75666.
92.
GuziewiczK, KomaromyA, IwabeS, et al.Sustained therapeutic reversal of canine bestrophinopathy with gene therapy using recombinant AAV2. Invest Ophthalmol Vis Sci, 2013; 54:5965.
93.
GuziewiczK, BeltranW, CideciyanA, et al.Gene therapy for bestrophinopathies. Acta Ophthalmol, 2014; 92.
94.
BennicelliJ, WrightJF, KomaromyA, et al.Reversal of blindness in animal models of Leber congenital amaurosis using optimized AAV2-mediated gene transfer. Mol Ther, 2008; 16:458–465.
95.
JacobsJB, Dell'ossoLF, HertleRW, et al.Gene therapy to abolish congenital nystagmus in RPE65-deficient canines. Invest Ophthalmol Vis Sci, 2003; 44:4249.
96.
JacobsJB, Dell'ossoLF, WangZI, et al.Using the NAFX to measure the effectiveness over time of gene therapy in canine LCA. Invest Ophthalmol Vis Sci, 2009; 50:4685–4692.
97.
NarfströmK, BragadottirR, RedmondTM, et al.Functional and structural evaluation after AAV.RPE65 gene transfer in the canine model of Leber's congenital amaurosis. Adv Exp Med Biol, 2003; 533:423–430.
98.
NarfströmK, SeeligerM, LaiCM, et al.Morphological aspects related to long-term functional improvement of the retina in the 4 years following rAAV-mediated gene transfer in the RPE65 null mutation dog. Adv Exp Med Biol, 2008; 613:139–146.
99.
NarfströmK, Vaegan, KatzM, et al.Assessment of structure and function over a 3-year period after gene transfer in RPE65-/- dogs. Doc Ophthalmol, 2005; 111:39–48.
100.
Petersen-JonesSM, AnnearMJ, BartoeJT, et al.Gene augmentation trials using the Rpe65-deficient dog: contributions towards development and refinement of human clinical trials. Adv Exp Med Biol, 2012; 723:177–182.
101.
DekomienG, RunteM, GoddeR, et al.Generalized progressive retinal atrophy of sloughi dogs is due to an 8-bp insertion in exon 21 of the PDE6B gene. Cytogenet Cell Genet, 2000; 90:261–267.
102.
GoldsteinO, MezeyJG, SchweitzerPA, et al.IQCB1 and PDE6B mutations cause similar early onset retinal degenerations in two closely related terrier dog breeds. Invest Ophthalmol Vis Sci, 2013; 54:7005–7019.
103.
KukekovaAV, GoldsteinO, JohnsonJL, et al.Canine RD3 mutation establishes rod–cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3. Mamm Genome, 2009; 20:109–123.
104.
GoldsteinO, KukekovaAV, AguirreGD, et al.Exonic SINE insertion in STK38l causes canine early retinal degeneration (erd). Genomics, 2010; 96:362–368.
105.
DownsLM, Wallin-HakanssonB, BoursnellM, et al.A frameshift mutation in golden retriever dogs with progressive retinal atrophy endorses SLC4A3 as a candidate gene for human retinal degenerations. PLoS One, 2011; 6:e21452.
106.
WinklerPA, EkenstedtKJ, OccelliLM, et al.A large animal model for CNGB1 autosomal recessive retinitis pigmentosa. PLoS One, 2013; 8:e72229.
107.
GoldsteinO, JordanJA, AguirreGD, et al.A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs. Mol Vis, 2013; 19:1871–1884.
108.
ZangerlB, GoldsteinO, PhilpAR, et al.Identical mutation in a novel retinal gene causes progressive rod–cone degeneration in dogs and retinitis pigmentosa in humans. Genomics, 2006; 88:551–563.
109.
DownsLM, BellJS, FreemanJ, et al.Late-onset progressive retinal atrophy in the Gordon and Irish setter breeds is associated with a frameshift mutation in C2orf71. Anim Genet, 2012; 44:169–177.
110.
GoldsteinO, MezeyJG, BoykoAR, et al.An ADAM9 mutation in canine cone–rod dystrophy 3 establishes homology with human cone–rod dystrophy 9. Mol Vis, 2010; 16:1549–1569.
111.
WiikAC, WadeC, BiagiT, et al.A deletion in nephronophthisis 4 (NPHP4) is associated with recessive cone–rod dystrophy in standard wire-haired dachshund. Genome Res, 2008; 18:1415–1421.
112.
DutrowEV, TanakaN, MiyaderaK, et al.A missense mutation in canine CNGA3 eliminates retinal cone function: a novel model for achromatopsia. Invest Ophthalmol Vis Sci, 2014; 55:1641.
113.
DekomienG, VollrathC, Petrasch-, ParwezE, et al.Progressive retinal atrophy in schapendoes dogs: mutation of the newly identified ccdc66 gen. Neurogenetics, 2010; 11:163–174.