All Title Author
Keywords Abstract

PLOS ONE  2014 

Natural History of Cone Disease in the Murine Model of Leber Congenital Amaurosis Due to CEP290 Mutation: Determining the Timing and Expectation of Therapy

DOI: 10.1371/journal.pone.0092928

Full-Text   Cite this paper   Add to My Lib

Abstract:

Background Mutations in the CEP290 (cilia-centrosomal protein 290 kDa) gene in Leber congenital amaurosis (LCA) cause early onset visual loss but retained cone photoreceptors in the fovea, which is the potential therapeutic target. A cone-only mouse model carrying a Cep290 gene mutation, rd16;Nrl?/?, was engineered to mimic the human disease. In the current study, we determined the natural history of retinal structure and function in this murine model to permit design of pre-clinical proof-of-concept studies and allow progress to be made toward human therapy. Analyses of retinal structure and visual function in CEP290-LCA patients were also performed for comparison with the results in the model. Methods Rd16;Nrl?/? mice were studied in the first 90 days of life with optical coherence tomography (OCT), electroretinography (ERG), retinal histopathology and immunocytochemistry. Structure and function data from a cohort of patients with CEP290-LCA (n = 15; ages 7–48) were compared with those of the model. Results CEP290-LCA patients retain a central island of photoreceptors with normal thickness at the fovea (despite severe visual loss); the extent of this island declined slowly with age. The rd16;Nrl?/? model also showed a relatively slow photoreceptor layer decline in thickness with ~80% remaining at 3 months. The number of pseudorosettes also became reduced. By comparison to single mutant Nrl?/? mice, UV- and M-cone ERGs of rd16;Nrl?/? were at least 1 log unit reduced at 1 month of age and declined further over the 3 months of monitoring. Expression of GNAT2 and S-opsin also decreased with age. Conclusions The natural history of early loss of photoreceptor function with retained cone cell nuclei is common to both CEP290-LCA patients and the rd16;Nrl?/? murine model. Pre-clinical proof-of-concept studies for uniocular therapies would seem most appropriate to begin with intervention at P35–40 and re-study after one month by assaying interocular difference in the UV-cone ERG.

References

[1]  den Hollander AI, Roepman R, Koenekoop RK, Cremers FP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27: 391–419. doi: 10.1016/j.preteyeres.2008.05.003
[2]  Drack AV, Lambert SR, Stone EM (2010) From the laboratory to the clinic: molecular genetic testing in pediatric ophthalmology. Am J Ophthalmol 149: 10–17. doi: 10.1016/j.ajo.2009.08.038
[3]  Jacobson SG, Sumaroka A, Luo X, Cideciyan AV (2013) Retinal optogenetic therapies: clinical criteria for candidacy. Clin Genet 84: 175–182. doi: 10.1111/cge.12165
[4]  Jacobson SG, Aleman TS, Cideciyan AV, Sumaroka A, Schwartz SB, et al. (2005) Identifying photoreceptors in blind eyes caused by RPE65 mutations: Prerequisite for human gene therapy success. Proc Natl Acad Sci USA 102: 6177–6182. doi: 10.1073/pnas.0500646102
[5]  Cideciyan AV (2010) Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy. Prog Retin Eye Res 29: 398–427. doi: 10.1016/j.preteyeres.2010.04.002
[6]  Cideciyan AV, Aleman TS, Jacobson SG, Khanna H, Sumaroka A, et al. (2007) Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosis. Hum Mutat 28: 1074–1083. doi: 10.1002/humu.20565
[7]  Cideciyan AV, Rachel RA, Aleman TS, Swider M, Schwartz SB, et al. (2011) Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. Hum Mol Genet 20: 1411–1423. doi: 10.1093/hmg/ddr022
[8]  Pasadhika S, Fishman GA, Stone EM, Lindeman M, Zelkha R, et al. (2010) Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis. Invest Ophthalmol Vis Sci 5: 2608–2614. doi: 10.1167/iovs.09-3734
[9]  Chang B, Khanna H, Hawes N, Jimeno D, He S, et al. (2006) In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum Mol Genet 15: 1847–1857. doi: 10.1093/hmg/ddl107
[10]  Rachel RA, Li T, Swaroop A (2012) Photoreceptor sensory cilia and ciliopathies: focus on CEP290, RPGR and their interacting proteins. Cilia 1: 22. doi: 10.1186/2046-2530-1-22
[11]  Cheng H, Aleman TS, Cideciyan AV, Khanna R, Jacobson SG, et al. (2006) In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development. Hum Mol Genet 15: 2588–2602. doi: 10.1093/hmg/ddl185
[12]  Aleman TS, Cideciyan AV, Aguirre GK, Huang WC, Mullins CL, et al. (2011) Human CRB1-associated retinal degeneration: comparison with the rd8 Crb1-mutant mouse model. Invest Ophthalmol Vis Sci 52: 6898–6910. doi: 10.1167/iovs.11-7701
[13]  Huang WC, Wright AF, Roman AJ, Cideciyan AV, Manson FD, et al. (2012) RPGR-associated retinal degeneration in human X-linked RP and a murine model. Invest Ophthalmol Vis Sci 53: 5594–608. doi: 10.1167/iovs.12-10070
[14]  Ruggeri M, Wehbe H, Jiao S, Gregori G, Jockovich ME, et al. (2007) In vivo three-dimensional high-resolution imaging of rodent retina with spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 48: 1808–1814. doi: 10.1167/iovs.06-0815
[15]  Boye SL, Conlon T, Erger K, Ryals R, Neeley A, et al. (2011) Long-term preservation of cone photoreceptors and restoration of cone function by gene therapy in the guanylate cyclase-1 knockout (GC1KO) mouse. Invest Ophthalmol Vis Sci 52: 7098–7108. doi: 10.1167/iovs.11-7867
[16]  Yzer S, Hollander AI, Lopez I, Pott JW, de Faber JT, et al. (2012) Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290. Mol Vis 18: 412–25.
[17]  McAnany JJ, Genead MA, Walia S, Drack AV, Stone EM, et al. (2013) Visual acuity changes in patients with leber congenital amaurosis and mutations in CEP290. JAMA Ophthalmol 131: 178–182. doi: 10.1001/2013.jamaophthalmol.354
[18]  Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Roman AJ, et al. (2008) Usher syndromes due to MYO7A, PCDH15, USH2A or GPR98 mutations share retinal disease mechanism. Hum Mol Genet 17: 2405–2415. doi: 10.1093/hmg/ddn140
[19]  Mears AJ, Kondo M, Swain PK, Takada Y, Bush RA, et al. (2001) Nrl is required for rod photoreceptor development. Nat Genet 29: 447–452. doi: 10.1038/ng774
[20]  Akhmedov NB, Piriev NI, Chang B, Rapoport AL, Hawes NL, et al. (2000) A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc Natl Acad Sci USA 97: 5551–5556. doi: 10.1073/pnas.97.10.5551
[21]  Mehalow AK, Kameya S, Smith RS, Hawes NL, Denegre JM, et al. (2003) CRB1 is essential for external limiting membrane integrity and photoreceptor morphogenesis in the mammalian retina. Hum Mol Genet 12: 2179–2189. doi: 10.1093/hmg/ddg232
[22]  Roger JE, Ranganath K, Zhao L, Cojocaru RI, Brooks M, et al. (2012) Preservation of cone photoreceptors after a rapid yet transient degeneration and remodeling in cone-only Nrl?/? mouse retina. J Neurosci 32: 528–541. doi: 10.1523/jneurosci.3591-11.2012
[23]  Murga-Zamalloa CA, Ghosh AK, Patil SB, Reed NA, Chan LS, et al. (2011) Accumulation of the Raf-1 kinase inhibitory protein (Rkip) is associated with Cep290-mediated photoreceptor degeneration in ciliopathies. J Biol Chem 286: 28276–28286. doi: 10.1074/jbc.m111.237560
[24]  Roman AJ, Boye SL, Aleman TS, Pang JJ, McDowell JH, et al. (2007) Electroretinographic analyses of RPE65-mutant rd12 mice: developing an in vivo bioassay for human gene therapy trials of Leber congenital amaurosis. Mol Vis 13: 1701–1710.
[25]  Fisher SK, Lewis GP, Linberg KA, Verardo MR (2005) Cellular remodeling in mammalian retina: results from studies of experimental retinal detachment. Prog Retin Eye Res 24: 395–431. doi: 10.1016/j.preteyeres.2004.10.004
[26]  Huang W, Li G, Qiu J, Gonzalez P, Challa P (2013) Protective effects of resveratrol in experimental retinal detachment. PLoS One 8: e75735. doi: 10.1371/journal.pone.0075735
[27]  Wenzel A, von Lintig J, Oberhauser V, Tanimoto N, Grimm C, et al. (2007) RPE65 is essential for the function of cone photoreceptors in NRL-deficient mice. Invest Ophthalmol Vis Sci 48: 534–542. doi: 10.1167/iovs.06-0652
[28]  Feathers KL, Lyubarsky AL, Khan NW, Teofilo K, Swaroop A, et al. (2008) Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments. Invest Ophthalmol Vis Sci 49: 1126–1135. doi: 10.1167/iovs.07-1234
[29]  Conley SM, Cai X, Makkia R, Wu Y, Sparrow JR, et al. (2012) Increased cone sensitivity to ABCA4 deficiency provides insight into macular vision loss in Stargardt’s dystrophy. Biochim Biophys Acta 1822: 1169–1179. doi: 10.1016/j.bbadis.2011.10.007
[30]  Khani SC, Pawlyk BS, Bulgakov OV, Kasperek E, Young JE, et al. (2007) AAV-mediated expression targeting of rod and cone photoreceptors with a human rhodopsin kinase promoter. Invest Ophthalmol Vis Sci 48: 3954–3961. doi: 10.1167/iovs.07-0257
[31]  Pang J, Tao Y, Boye S, Li J, Deng W, et al.. (2013) AAV-mediated gene therapy restores cone function in the Cnga3/Nrl double knockout mouse. Invest Ophthalmol Vis Sci 54: E-Abstract 2723.
[32]  Nicoud M, Kong J, Iqball S, Kan O, Naylor S, et al. (2007) Development of photoreceptor-specific promoters and their utility to investigate EIAV lentiviral vector mediated gene transfer to photoreceptors. J Gene Med 9: 1015–1023. doi: 10.1002/jgm.1115
[33]  Kong J, Kim SR, Binley K, Pata I, Doi K, et al. (2008) Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther 15: 1311–1320. doi: 10.1038/gt.2008.78
[34]  Pang J, Cheng M, Haire SE, Barker E, Planelles V, et al. (2006) Efficiency of lentiviral transduction during development in normal and rd mice. Mol Vis 12: 756–767.
[35]  Bainbridge JW, Stephens C, Parsley K, Demaison C, Halfyard A, et al. (2001) In vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium. Gene Ther 8: 1665–1668. doi: 10.1038/sj.gt.3301574
[36]  Balaggan KS, Binley K, Esapa M, Iqball S, Askham Z, et al. (2006) Stable and efficient intraocular gene transfer using pseudotyped EIAV lentiviral vectors. J Gene Med 8: 275–285. doi: 10.1002/jgm.845
[37]  Miyoshi H, Takahashi M, Gage FH, Verma IM (1997) Stable and efficient gene transfer into the retina using an HIV-based lentiviral vector. Proc Natl Acad Sci USA 94: 10319–10323. doi: 10.1073/pnas.94.19.10319
[38]  Greenberg KP, Lee ES, Schaffer DV, Flannery JG (2006) Gene delivery to the retina using lentiviral vectors. Adv Exp Med Biol 572: 255–266. doi: 10.1007/0-387-32442-9_36
[39]  Bemelmans AP, Bonnel S, Houhou L, Dufour N, Nandrot E, et al. (2005) Retinal cell type expression specificity of HIV-1-derived gene transfer vectors upon subretinal injection in the adult rat: influence of pseudotyping and promoter. J Gene Med 7: 1367–1374. doi: 10.1002/jgm.788
[40]  Binley K, Widdowson P, Loader J, Kelleher M, Iqball S, et al. (2013) Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease. Invest Ophthalmol Vis Sci 54: 4061–4071. doi: 10.1167/iovs.13-11871
[41]  Alexander JJ, Umino Y, Everhart D, Chang B, Min SH, et al. (2007) Restoration of cone vision in a mouse model of achromatopsia. Nat Med 13: 685–687. doi: 10.1038/nm1596
[42]  Mancuso K, Hauswirth WW, Li Q, Connor TB, Kuchenbecker JA, et al. (2009) Gene therapy for red-green colour blindness in adult primates. Nature 461: 784–787. doi: 10.1038/nature08401
[43]  Komáromy AM, Alexander JJ, Rowlan JS, Garcia MM, Chiodo VA, et al. (2010) Gene therapy rescues cone function in congenital achromatopsia. Hum Mol Genet 19: 2581–2593. doi: 10.1093/hmg/ddq136
[44]  Boye SE, Alexander JJ, Boye SL, Witherspoon CD, Sandefer KJ, et al. (2012) The human rhodopsin kinase promoter in an AAV5 vector confers rod- and cone-specific expression in the primate retina. Hum Gene Ther 23: 1101–1115. doi: 10.1089/hum.2012.125
[45]  Boye SE, Boye SL, Lewin AS, Hauswirth WW (2013) A comprehensive review of retinal gene therapy. Mol Ther 21: 509–519. doi: 10.1038/mt.2012.280
[46]  Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, et al. (2008) Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med 358: 2231–2239. doi: 10.1056/nejmoa0802268
[47]  Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, 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. 19: 979–990. doi: 10.1089/hum.2008.107
[48]  Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, et al. (2008) Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA 105: 15112–15117. doi: 10.1073/pnas.0807027105
[49]  Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, et al. (2008) Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med 358: 2240–2248. doi: 10.1056/nejmoa0802315
[50]  Dong B, Nakai H, Xiao W (2010) Characterization of genome integrity for oversized recombinant AAV vector. Mol Ther 18: 87–92. doi: 10.1038/mt.2009.258
[51]  Lai Y, Yue Y, Duan D (2010) Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome>or = 8.2 kb. Mol Ther 18: 75–79. doi: 10.1038/mt.2009.256
[52]  Wu Z, Yang H, Colosi P (2010) Effect of genome size on AAV vector packaging. Mol Ther 18: 80–86. doi: 10.1038/mt.2009.255
[53]  Kapranov P, Chen L, Dederich D, Dong B, He J, et al. (2012) Native molecular state of adeno-associated viral vectors revealed by single-molecule sequencing. Hum Gene Ther 23: 46–55. doi: 10.1089/hum.2011.160
[54]  Allocca M, Doria M, Petrillo M, Colella P, Garcia-Hoyos M, et al. (2008) Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. J Clin Invest 118: 1955–1964. doi: 10.1172/jci34316
[55]  Lopes VS, Boye SE, Louie CM, Boye S, Dyka F, et al. (2013) Retinal gene therapy with a large MYO7A cDNA using adeno-associated virus. Gene Ther 20: 824–833. doi: 10.1038/gt.2013.3
[56]  Colella P, Sommella A, Marrocco E, Di Vicino U, Polishchuk E, et al. (2013) Myosin7a deficiency results in reduced retinal activity which is improved by gene therapy. PloS One 8: e72027. doi: 10.1371/journal.pone.0072027
[57]  Lai Y, Yue Y, Liu M, Ghosh A, Engelhardt JF, et al. (2005) Efficient in vivo gene expression by trans-splicing adeno-associated viral vectors. Nat Biotechnol 23: 1435–1439. doi: 10.1038/nbt1153
[58]  Lai Y, Li D, Yue Y, Duan D (2008) Design of trans-splicing adeno-associated viral vectors for Duchenne muscular dystrophy gene therapy. Methods Mol Biol 433: 259–275. doi: 10.1007/978-1-59745-237-3_16
[59]  Lostal W, Bartoli M, Bourg N, Roudaut C, Benta?b A, et al. (2010) Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer. Hum Mol Genet 19: 1897–1907. doi: 10.1093/hmg/ddq065
[60]  Zhang Y, Duan D (2012) Novel mini-dystrophin gene dual adeno-associated virus vectors restore neuronal nitric oxide synthase expression at the sarcolemma. Hum Gene Ther 23: 98–103. doi: 10.1089/hum.2011.131
[61]  Halbert CL, Allen JM, Miller AD (2002) Efficient mouse airway transduction following recombination between AAV vectors carrying parts of a larger gene. Nat Biotechnol 20: 697–701. doi: 10.1038/nbt0702-697
[62]  Duan D, Yue Y, Engelhardt JF (2001) Expanding AAV packaging capacity with trans-splicing or overlapping vectors: a quantitative comparison. Mol Ther 4: 383–391. doi: 10.1006/mthe.2001.0456
[63]  Duan D, Yue Y, Yan Z, Engelhardt JF (2003) Trans-splicing vectors expand the packaging limits of adeno-associated virus for gene therapy applications. Methods Mol Med 76: 287–307. doi: 10.1385/1-59259-304-6:287
[64]  Yan Z, Zhang Y, Duan D, Engelhardt JF (2000) Trans-splicing vectors expand the utility of adeno-associated virus for gene therapy. Proc Natl Acad Sci USA 97: 6716–6721. doi: 10.1073/pnas.97.12.6716
[65]  Yan Z, Ritchie TC, Duan D, Engelhardt JF (2002) Recombinant AAV-mediated gene delivery using dual vector heterodimerization. Methods Enzymol 346: 334–357. doi: 10.1016/s0076-6879(02)46065-x
[66]  Baye LM, Patrinostro X, Swaminathan S, Beck JS, Zhang Y, et al. (2011) The N-terminal region of centrosomal protein 290 (CEP290) restores vision in a zebrafish model of human blindness. Hum Mol Genet 20: 1467–1477. doi: 10.1093/hmg/ddr025
[67]  Sch?fer T, Pütz M, Lienkamp S, Ganner A, Bergbreiter A, et al. (2008) Genetic and physical interaction between the NPHP5 and NPHP6 gene products. Hum Mol Genet 17: 3655–3662. doi: 10.1093/hmg/ddn260
[68]  Drivas TG, Holzbaur EL, Bennett J (2013) Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration. J Clin Invest 123: 4525–4539. doi: 10.1172/jci69448

Full-Text

comments powered by Disqus