The status and progress in gene therapy study of Stargardt disease_Chinese Journal of Ocular Fundus Diseases

Authors：

HeYing ,  DaiXufeng , ZhangHua , PangJijing

School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou 325027, China;

Corresponding author：

DaiXufeng, Email: daixufeng@sohu.com

Keywords：

Macular Degenerationcongenital/congenital; Gene therapy; Disease models, animal; Review

DOI：

10.3760/cma.j.issn.1005-1015.2016.02.029

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Stargardt disease (STGD) is an inherited disorder of retinal pigment epithelium. Three genes have been found to be implicated in STGD including Abca4 (adenosine triphosphate-binding cassette, sub-family A, member 4), Elovl4 (elongation of very long chain fatty acids protein 4) and Prom1 (prominin-1). Target genes can be delivered to the retina by various methods such as lentivirus (LV) vectors, adeno-associated virus (AAV) vectors and non-viral nano-particles. The Abca4^-/-, Elovl4^-/- and Prom1^-/- mice model are used to study the pathogenesis mechanism and treatment of STGD. Retinal function improved significantly upon gene therapy in these models. Based on these works using animal model, phase Ⅰ/Ⅱa clinical trial of Abca4-associated STGD gene therapy are underway. AsaLV vector, equine infectious anemia virus (EIAV) is used to carry the Abca4 gene. These studies will evaluate three dose levels of the EIAV vector for safety, tolerability and biological activity. Moreover, some preclinical attempts to deliver Abca4 via AAV have been made usingamodified AAV vectors because of the large size of the ABCA4 cDNA. The good responses in animal models render STGDavery attractive object for human gene therapy after the successful of the phase Ⅰ/Ⅱ clinical trials of Leber′s congenital amaurosis.

Citation： HeYing, DaiXufeng, ZhangHua, PangJijing. The status and progress in gene therapy study of Stargardt disease. Chinese Journal of Ocular Fundus Diseases, 2016, 32(2): 224-227. doi: 10.3760/cma.j.issn.1005-1015.2016.02.029 Copy

1.	Bax NM, Sangermano R, Roosing S, et al. Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant [J]. Hum Mutat, 2015, 36(1):43-47. DOI: 10.1002/humu.22717.
2.	Dellett M, Sasai N, Nishide K, et al. Genetic background and light-dependent progression of photoreceptor cell degeneration in Prominin-1 knockout mice [J]. Invest Ophthalmol Vis Sci, 2014, 56(1):164-176. DOI: 10.1167/iovs.14-15479.
3.	Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies [J]. Prog Retin Eye Res, 2014, 43:108-128. DOI: 10.1016/j.preteyeres.2014.08.001.
4.	Logan S, Anderson RE. Dominant stargardt macular dystrophy (STGD3) and ELOVL4 [J]. Adv Exp Med Biol, 2014, 801:447-453. DOI: 10.1007/978-1-4614-3209-8_57.
5.	Yang Z, Chen Y, Lillo C, et al. Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice [J].JClin Invest, 2008, 118(8):2908-2916. DOI: 10.1172/JCI35891.
6.	Zhang X, Ge X, Shi W, et al. Molecular diagnosis of putative Stargardt disease by capture next generation sequencing [J/OL]. PLoS One, 2014, 9(4):95528[2014-04-24]. http://dx.plos.org/10.1371/journal.pone.0095528. DOI: 10.1371/journal.pone.0095528.
7.	Haji Abdollahi S, Hirose T. Stargardt-fundus flavimaculatus: recent advancements and treatment [J]. Semin Ophthalmol, 2013, 28(5-6):372-376. DOI: 10.3109/08820538.2013.825286.
8.	Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease [J]. Adv Exp Med Biol, 2010, 703:105-125. DOI: 10.1007/978-1-4419-5635-4_8.
9.	Harkewicz R, Du H, Tong Z, et al. Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function [J].JBiol Chem, 2012, 287(14):11469-11480. DOI: 10.1074/jbc.M111.256073.
10.	Rotstein NP, Politi LE, German OL, et al. Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors [J]. Invest Ophthalmol Vis Sci, 2003, 44(5):2252-2259.
11.	Han Z, Conley SM, Makkia RS, et al. DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice [J].JClin Invest, 2012, 122(9):3221-3226. DOI: 10.1172/JCI64833.
12.	Conley SM, Cai X, Makkia R, et al. Increased cone sensitivity to ABCA4 deficiency provides insight into macular vision loss in Stargardt′s dystrophy [J]. Biochim Biophys Acta, 2012, 1822(7):1169-1179. DOI: 10.1016/j.bbadis.2011.10.007.
13.	Quazi F, Molday RS. ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal [J]. Proc Natl Acad Sci USA, 2014, 111(13):5024-5029. DOI: 10.1073/pnas.1400780111.
14.	Barabas P, Liu A, Xing W, et al. Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration [J]. Proc Natl Acad Sci USA, 2013, 110(13):5181-5186. DOI: 10.1073/pnas.1214707110.
15.	Kuny S, Filion MA, Suh M, et al. Long-term retinal cone survival and delayed alteration of the cone mosaic inatransgenic mouse model of stargardt-like dystrophy (STGD3) [J]. Invest Ophthalmol Vis Sci, 2014, 55(1):424-439. DOI: 10.1167/iovs.13-13457.
16.	Mata NL, Weng J, Travis GH. Biosynthesis ofamajor lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration [J]. Proc Natl Acad Sci USA, 2000, 97(13):7154-7159.
17.	Karan G, Lillo C, Yang Z, et al. Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice:amodel for macular degeneration [J]. Proc Natl Acad Sci USA, 2005, 102(11):4164-4169.
18.	Karan G, Yang ZL, Zhang K. Expression of wild type and mutant ELOVL4 in cell culture: subcellular localization and cell viability [J]. Mol Vis, 2004, 10:248-253.
19.	Zhang K, Kniazeva M, Han M, et al. A5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy [J]. Nat Genet, 2001, 27(1):89-93.
20.	Pang JJ, Lei L, Dai X, et al. AAV-mediated gene therapy in mouse models of recessive retinal degeneration [J]. Curr Mol Med, 2012, 12(3):316-330.
21.	Kong J, Kim SR, Binley K, et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy [J]. Gene Ther, 2008, 15(19):1311-1320. DOI: 10.1038/gt.2008.78.
22.	Allocca M, Doria M, Petrillo M, et al. Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice [J].JClin Invest, 2008, 118(5):1955-1964. DOI: 10.1172/JCI34316.
23.	Charbel Issa P, De Silva SR, Lipinski DM, et al. Assessment of tropism and effectiveness of new primate-derived hybrid recombinant AAV serotypes in the mouse and primate retina [J/OL]. PLoS One, 2013, 8(4):60361[2013-04-09]. http://dx.plos.org/10.1371/journal.pone.0060361.DOI: 10.1371/journal.pone.0060361 .
24.	Trapani I, Colella P, Sommella A, et al. Effective delivery of large genes to the retina by dual AAV vectors [J]. EMBO Mol Med, 2014, 6(2):194-211. DOI: 10.1002/emmm.201302948.
25.	Han Z, Conley SM, Naash MI. Gene therapy for Stargardt disease associated with ABCA4 gene [J]. Adv Exp Med Biol, 2014, 801:719-724. DOI: 10.1007/978-1-4614-3209-8_90.
26.	Sarkis C, Philippe S, Mallet J, et al. Non-integrating lentiviral vectors [J]. Curr Gene Ther, 2008, 8(6):430-437.
27.	Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber′s congenital amaurosis [J].NEnglJMed, 2008, 358(21):2240-2248. DOI: 10.1056/NEJMoa0802315.
28.	Cai X, Conley SM, Nash Z, et al. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype inamouse model of retinitis pigmentosa [J]. FASEB J, 2010, 24(4):1178-1191. DOI:10.1096/fj.09-139147.
29.	Han Z, Conley SM, Makkia R, et al. Comparative analysis of DNA nanoparticles and AAVs for ocular gene delivery [J/OL]. PLoS One, 2012, 7(12):52189[2012-12-18]. http://dx.plos.org/10.1371/journal.pone.0052189. DOI: 10.1371/journal.pone.0052189.
30.	Binley K, Widdowson P, Loader J, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease [J]. Invest Ophthalmol Vis Sci, 2013, 54(6):4061-4071. DOI: 10.1167/iovs.13-11871.
31.	Boye SE, Boye SL, Lewin AS, et al. Acomprehensive review of retinal gene therapy [J]. Mol Ther, 2013, 21(3):509-519. DOI: 10.1038/mt.2012.280.

1. Bax NM, Sangermano R, Roosing S, et al. Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant [J]. Hum Mutat, 2015, 36(1):43-47. DOI: 10.1002/humu.22717.
2. Dellett M, Sasai N, Nishide K, et al. Genetic background and light-dependent progression of photoreceptor cell degeneration in Prominin-1 knockout mice [J]. Invest Ophthalmol Vis Sci, 2014, 56(1):164-176. DOI: 10.1167/iovs.14-15479.
3. Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies [J]. Prog Retin Eye Res, 2014, 43:108-128. DOI: 10.1016/j.preteyeres.2014.08.001.
4. Logan S, Anderson RE. Dominant stargardt macular dystrophy (STGD3) and ELOVL4 [J]. Adv Exp Med Biol, 2014, 801:447-453. DOI: 10.1007/978-1-4614-3209-8_57.
5. Yang Z, Chen Y, Lillo C, et al. Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice [J].JClin Invest, 2008, 118(8):2908-2916. DOI: 10.1172/JCI35891.
6. Zhang X, Ge X, Shi W, et al. Molecular diagnosis of putative Stargardt disease by capture next generation sequencing [J/OL]. PLoS One, 2014, 9(4):95528[2014-04-24]. http://dx.plos.org/10.1371/journal.pone.0095528. DOI: 10.1371/journal.pone.0095528.
7. Haji Abdollahi S, Hirose T. Stargardt-fundus flavimaculatus: recent advancements and treatment [J]. Semin Ophthalmol, 2013, 28(5-6):372-376. DOI: 10.3109/08820538.2013.825286.
8. Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease [J]. Adv Exp Med Biol, 2010, 703:105-125. DOI: 10.1007/978-1-4419-5635-4_8.
9. Harkewicz R, Du H, Tong Z, et al. Essential role of ELOVL4 protein in very long chain fatty acid synthesis and retinal function [J].JBiol Chem, 2012, 287(14):11469-11480. DOI: 10.1074/jbc.M111.256073.
10. Rotstein NP, Politi LE, German OL, et al. Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors [J]. Invest Ophthalmol Vis Sci, 2003, 44(5):2252-2259.
11. Han Z, Conley SM, Makkia RS, et al. DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice [J].JClin Invest, 2012, 122(9):3221-3226. DOI: 10.1172/JCI64833.
12. Conley SM, Cai X, Makkia R, et al. Increased cone sensitivity to ABCA4 deficiency provides insight into macular vision loss in Stargardt′s dystrophy [J]. Biochim Biophys Acta, 2012, 1822(7):1169-1179. DOI: 10.1016/j.bbadis.2011.10.007.
13. Quazi F, Molday RS. ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal [J]. Proc Natl Acad Sci USA, 2014, 111(13):5024-5029. DOI: 10.1073/pnas.1400780111.
14. Barabas P, Liu A, Xing W, et al. Role of ELOVL4 and very long-chain polyunsaturated fatty acids in mouse models of Stargardt type 3 retinal degeneration [J]. Proc Natl Acad Sci USA, 2013, 110(13):5181-5186. DOI: 10.1073/pnas.1214707110.
15. Kuny S, Filion MA, Suh M, et al. Long-term retinal cone survival and delayed alteration of the cone mosaic inatransgenic mouse model of stargardt-like dystrophy (STGD3) [J]. Invest Ophthalmol Vis Sci, 2014, 55(1):424-439. DOI: 10.1167/iovs.13-13457.
16. Mata NL, Weng J, Travis GH. Biosynthesis ofamajor lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration [J]. Proc Natl Acad Sci USA, 2000, 97(13):7154-7159.
17. Karan G, Lillo C, Yang Z, et al. Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice:amodel for macular degeneration [J]. Proc Natl Acad Sci USA, 2005, 102(11):4164-4169.
18. Karan G, Yang ZL, Zhang K. Expression of wild type and mutant ELOVL4 in cell culture: subcellular localization and cell viability [J]. Mol Vis, 2004, 10:248-253.
19. Zhang K, Kniazeva M, Han M, et al. A5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy [J]. Nat Genet, 2001, 27(1):89-93.
20. Pang JJ, Lei L, Dai X, et al. AAV-mediated gene therapy in mouse models of recessive retinal degeneration [J]. Curr Mol Med, 2012, 12(3):316-330.
21. Kong J, Kim SR, Binley K, et al. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy [J]. Gene Ther, 2008, 15(19):1311-1320. DOI: 10.1038/gt.2008.78.
22. Allocca M, Doria M, Petrillo M, et al. Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice [J].JClin Invest, 2008, 118(5):1955-1964. DOI: 10.1172/JCI34316.
23. Charbel Issa P, De Silva SR, Lipinski DM, et al. Assessment of tropism and effectiveness of new primate-derived hybrid recombinant AAV serotypes in the mouse and primate retina [J/OL]. PLoS One, 2013, 8(4):60361[2013-04-09]. http://dx.plos.org/10.1371/journal.pone.0060361.DOI: 10.1371/journal.pone.0060361 .
24. Trapani I, Colella P, Sommella A, et al. Effective delivery of large genes to the retina by dual AAV vectors [J]. EMBO Mol Med, 2014, 6(2):194-211. DOI: 10.1002/emmm.201302948.
25. Han Z, Conley SM, Naash MI. Gene therapy for Stargardt disease associated with ABCA4 gene [J]. Adv Exp Med Biol, 2014, 801:719-724. DOI: 10.1007/978-1-4614-3209-8_90.
26. Sarkis C, Philippe S, Mallet J, et al. Non-integrating lentiviral vectors [J]. Curr Gene Ther, 2008, 8(6):430-437.
27. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber′s congenital amaurosis [J].NEnglJMed, 2008, 358(21):2240-2248. DOI: 10.1056/NEJMoa0802315.
28. Cai X, Conley SM, Nash Z, et al. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype inamouse model of retinitis pigmentosa [J]. FASEB J, 2010, 24(4):1178-1191. DOI:10.1096/fj.09-139147.
29. Han Z, Conley SM, Makkia R, et al. Comparative analysis of DNA nanoparticles and AAVs for ocular gene delivery [J/OL]. PLoS One, 2012, 7(12):52189[2012-12-18]. http://dx.plos.org/10.1371/journal.pone.0052189. DOI: 10.1371/journal.pone.0052189.
30. Binley K, Widdowson P, Loader J, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease [J]. Invest Ophthalmol Vis Sci, 2013, 54(6):4061-4071. DOI: 10.1167/iovs.13-11871.
31. Boye SE, Boye SL, Lewin AS, et al. Acomprehensive review of retinal gene therapy [J]. Mol Ther, 2013, 21(3):509-519. DOI: 10.1038/mt.2012.280.

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