腺相关病毒载体在视网膜色素变性基因治疗中的应用研究进展_Chinese Journal of Ocular Fundus Diseases

Authors：

李光辉 , 曾芳 , 王晔恺 ,  黎运呈 , 宋毅果

316004 浙江省舟山医院眼科中心(李光辉)、细胞分子实验室(曾芳)、检验科(王晔恺)、传染科(黎运呈);

Corresponding author：

黎运呈, Email: mylyc2005@yahoo.cn

Keywords：

色素性视网膜炎/治疗; 基因疗法; 综述

DOI：

10.3760/cam.j.issn.1005-1015.2014.06.031

Video：

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基因治疗是视网膜色素变性(RP)治疗研究的热点之一。经动物实验及临床试验证实, 腺相关病毒(AAV)载体因其无致病性、宿主范围广、转染和表达效率高、目的基因长期表达等优点成为视网膜疾病基因治疗的重要载体。但如何建立安全有效的基因治疗导入系统是目前临床需要首要解决的问题。此外, 由于基因的导向性和表达的调控性较为局限, 也限制了AAV载体介导的基因治疗在临床的广泛应用。进一步深入研究AAV的病毒生物学基础, 设计更多的组织特异性启动子以提高AAV载体的转染效率、靶向能力和安全性将为RP基因治疗带来新的曙光。

Citation： 李光辉, 曾芳, 王晔恺, 黎运呈, 宋毅果. 腺相关病毒载体在视网膜色素变性基因治疗中的应用研究进展. Chinese Journal of Ocular Fundus Diseases, 2014, 30(6): 636-639. doi: 10.3760/cam.j.issn.1005-1015.2014.06.031 Copy

1.	Hamel C. Retinitis pigmentosa[J]. Orphanet J Rare Dis, 2006, 11:40.
2.	Lai Y, Yue Y, Duan D. Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome > or=8.2 kb[J]. Mol Ther, 2010, 18:75-79.
3.	Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness[J]. Nature Genet, 2001, 28:92-95.
4.	Acland GM, Aguirre GD, 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[J]. Mol Ther, 2005, 12:1072-1082.
5.	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[J]. Mol Ther, 2003, 7:774-781.
6.	Le Meur G, Stieger K, Smith AJ, et al. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium[J]. Gene Ther, 2007, 14:292-303.
7.	Bennicelli J, Wright JF, Komaromy A, et al. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer[J].Mol Ther, 2008, 16:458-465.
8.	Inglehearn CF, Keen TJ, Bashir R, et al. A completed screen for mutations of the rhodopsin gene in a panel of patients with autosomal dominant retinitis pigmentosa[J]. Hum Mol Genet, 1992, 1:41-45.
9.	Pang JJ, Dai X, Boye SE, et al. Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa[J]. Mol Ther, 2011, 19:234-242.
10.	Yao J, Jia L, Khan N, et al. Caspase inhibition with XIAP as an adjunct to AAV vector gene-replacement therapy:improving efficacy and prolonging the treatment window[J]. PLoS One, 2012, 7:37197[2012-05-16].http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0037197.
11.	Petit L, Lhériteau E, Weber M, et al. Restoration of vision in the PDE6β-deficient dog, a large animal model of rod-cone dystrophy[J].Mol Ther, 2012, 20:2019-2130.
12.	Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis[J]. N Engl J Med, 2008, 358:2240-2248.
13.	Kiang AS, Palfi A, Ader M, et al.Toward a gene therapy for dominant disease:validation of an RNA interference-based mutation-independent approach[J]. Mol Ther, 2005, 12:555-561.
14.	Gorbatyuk M, Justilien V, Liu J, et al.Suppression of mouse RHOdopsin expression in vivo by AAV mediated siRNA delivery[J]. Vision Res, 2007, 47:1202-1208.
15.	Millington-Ward S, Chadderton N, O'Reilly M, et al. Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa[J]. Mol Ther, 2011, 19:642-649.
16.	Mao H, Gorbatyuk MS, Rossmiller B, et al.Long-term rescue of retinal structure and function by RHOdopsin RNA replacement with a single adeno-associated viral vector in P23H RHO transgenic mice[J]. Hum Gene Ther, 2012, 23:356-366.
17.	Hammann C, Westhof E.Seaching genomes for ribozymes and riboswitches[J]. Genome Biology, 2007, 8:210.
18.	Drenser KA, Timmers AM, Hauswirth WW, et al.Ribozyme-targeted destruction of RNA associated with autosomal-dominant retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 1998, 39:681-689.
19.	O'Neill B, Millington-Ward S, O'Reilly M, et al.Ribozyme-based therapeutic approaches for autosomal dominant retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2000, 41:2863-2869.
20.	Shaw LC, Skold A, Wong F, et al. An allele-specific hammerhead ribozyme gene therapy for a porcine model of autosomal dominant retinitis pigmentosa[J].Mol Vis, 2001, 7:6-13.
21.	Gorbatyuk M, Justilien V, Liu J, et al. Preservation of Photoreceptor morphology and function in P23H rats using an allele independent ribozyme[J]. Exp Eye Res, 2007, 84:44-52.
22.	Sullivan JM, Pietras KM, Shin BJ, et al. Hammerhead ribozymes designed to cleave all human rod opsin mRNAs which cause autosomal dominant retinitis pigmentosa[J]. Mol Vis, 2002, 8:102-113.
23.	Gorbatyuk M, Justilien V, Liu J, et al. Suppression of mouse RHOdopsin expression in vivo by AAV mediated siRNA delivery[J]. Vision Res, 2007, 47:1202-1208.
24.	Chakraborty D, Whalen P, Lewin AS, et al.In vitro analysis of ribozyme-mediated knockdown of an ADRP associated RHOdopsin mutation[J]. Adv Exp Med Biol, 2008, 613:97-106.
25.	Leonard KC, Petrin D, Coupland SG, et al. XIAP protection of photoreceptors in animal models of retinitis pigmentosa[J/OL].PLoS One, 2007, 2:314[2007-03-21].http://dx.plos.org/10.1371/journal.pone.0000314.
26.	Comitato A, Sanges D1, Rossi A, et al. Activation of Bax in three models of retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2014, 55:3555-3562.
27.	Nir I, Kedzierski W, Chen J, et al. Expression of Bcl-2 protects against photoreceptor degeneration in retinal degeneration slow (rds) mice[J].J Neurosci, 2000, 20:2150-2154.
28.	Tsang SH, Chen J, Kjeldbye H, et al. Retarding photoreceptor degeneration in Pdegtm1/Pdegtml mice by an apoptosis suppressor gene[J]. Invest Ophthalmol Vis Sci, 1997, 38:943-950.
29.	Cayouette M, Behn D, Sendtner M, et al. Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse[J]. J Neurosci, 1998, 18:9282-9293.
30.	Liang FQ, Aleman TS, Dejneka NS, et al. Long-term protection of retinal structure but not function using RAAV CNTF in animal models of retinitis pigmentosa[J]. Mol Ther, 2001, 4:461-472.
31.	Bok D, Yasumura D, Matthes MT, et al.Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation[J]. Exp Res, 2002, 74:719-735.
32.	Rhee KD, Ruiz A, Duncan JL, et al.Molecular and cellular alterations induced by sustained expression of ciliary neurotrophic factor in a mouse model of retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2007, 48:1389-1400.
33.	McGee Sanftner LH, Abel H, Hauswirth WW, et al.Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa[J].Mol Ther, 2001, 4:622-629.
34.	Lawrence JM, Keegan DJ, Muir EM, et al.Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons rats[J].Invest Ophthalmol Vis Sci, 2004, 45:267-274.
35.	Andrieu-Soler C, Aubert-Pouessel A, Doat M, et al. Intravitreous injection of PLGA micrespheres encapsulating GDNF promotes the survival of photoreceptors in the rd1/rd1 mouse[J].Mol Vis, 2005, 11:1002-1011.
36.	Buch PK, MacLaren RE, 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[J]. Mol Ther, 2006, 14:700-709.
37.	Lau D, McGee LH, Zhou S, et al.Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2[J].Invest Ophthalmol Vis Sci, 2000, 41:3622-3633.
38.	Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis[J]. N Engl J Med, 2008, 358:2231-2239.
39.	Cideciyan AV, Hauswirth WW, Aleman TS, et al. Vision 1 year after gene therapy for Leber's congenital amaurosis[J]. N Engl J Med, 2009, 361:725-727.
40.	Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18:643-650.
41.	Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis:a phase 1 dose-escalation trial[J]. Lancet, 2009, 374:1597-1605.
42.	Cideciyan AV, Hauswirth WW, Aleman TS, et al. Human RPE65 gene therapy for Leber congenital amaurosis:persistence of early visual improvements and safety at 1 year[J]. Hum Gene Ther, 2009, 20:999-1004.
43.	Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18:643-650.

1. Hamel C. Retinitis pigmentosa[J]. Orphanet J Rare Dis, 2006, 11:40.
2. Lai Y, Yue Y, Duan D. Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome > or=8.2 kb[J]. Mol Ther, 2010, 18:75-79.
3. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of childhood blindness[J]. Nature Genet, 2001, 28:92-95.
4. Acland GM, Aguirre GD, 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[J]. Mol Ther, 2005, 12:1072-1082.
5. 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[J]. Mol Ther, 2003, 7:774-781.
6. Le Meur G, Stieger K, Smith AJ, et al. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium[J]. Gene Ther, 2007, 14:292-303.
7. Bennicelli J, Wright JF, Komaromy A, et al. Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer[J].Mol Ther, 2008, 16:458-465.
8. Inglehearn CF, Keen TJ, Bashir R, et al. A completed screen for mutations of the rhodopsin gene in a panel of patients with autosomal dominant retinitis pigmentosa[J]. Hum Mol Genet, 1992, 1:41-45.
9. Pang JJ, Dai X, Boye SE, et al. Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa[J]. Mol Ther, 2011, 19:234-242.
10. Yao J, Jia L, Khan N, et al. Caspase inhibition with XIAP as an adjunct to AAV vector gene-replacement therapy:improving efficacy and prolonging the treatment window[J]. PLoS One, 2012, 7:37197[2012-05-16].http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0037197.
11. Petit L, Lhériteau E, Weber M, et al. Restoration of vision in the PDE6β-deficient dog, a large animal model of rod-cone dystrophy[J].Mol Ther, 2012, 20:2019-2130.
12. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis[J]. N Engl J Med, 2008, 358:2240-2248.
13. Kiang AS, Palfi A, Ader M, et al.Toward a gene therapy for dominant disease:validation of an RNA interference-based mutation-independent approach[J]. Mol Ther, 2005, 12:555-561.
14. Gorbatyuk M, Justilien V, Liu J, et al.Suppression of mouse RHOdopsin expression in vivo by AAV mediated siRNA delivery[J]. Vision Res, 2007, 47:1202-1208.
15. Millington-Ward S, Chadderton N, O'Reilly M, et al. Suppression and replacement gene therapy for autosomal dominant disease in a murine model of dominant retinitis pigmentosa[J]. Mol Ther, 2011, 19:642-649.
16. Mao H, Gorbatyuk MS, Rossmiller B, et al.Long-term rescue of retinal structure and function by RHOdopsin RNA replacement with a single adeno-associated viral vector in P23H RHO transgenic mice[J]. Hum Gene Ther, 2012, 23:356-366.
17. Hammann C, Westhof E.Seaching genomes for ribozymes and riboswitches[J]. Genome Biology, 2007, 8:210.
18. Drenser KA, Timmers AM, Hauswirth WW, et al.Ribozyme-targeted destruction of RNA associated with autosomal-dominant retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 1998, 39:681-689.
19. O'Neill B, Millington-Ward S, O'Reilly M, et al.Ribozyme-based therapeutic approaches for autosomal dominant retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2000, 41:2863-2869.
20. Shaw LC, Skold A, Wong F, et al. An allele-specific hammerhead ribozyme gene therapy for a porcine model of autosomal dominant retinitis pigmentosa[J].Mol Vis, 2001, 7:6-13.
21. Gorbatyuk M, Justilien V, Liu J, et al. Preservation of Photoreceptor morphology and function in P23H rats using an allele independent ribozyme[J]. Exp Eye Res, 2007, 84:44-52.
22. Sullivan JM, Pietras KM, Shin BJ, et al. Hammerhead ribozymes designed to cleave all human rod opsin mRNAs which cause autosomal dominant retinitis pigmentosa[J]. Mol Vis, 2002, 8:102-113.
23. Gorbatyuk M, Justilien V, Liu J, et al. Suppression of mouse RHOdopsin expression in vivo by AAV mediated siRNA delivery[J]. Vision Res, 2007, 47:1202-1208.
24. Chakraborty D, Whalen P, Lewin AS, et al.In vitro analysis of ribozyme-mediated knockdown of an ADRP associated RHOdopsin mutation[J]. Adv Exp Med Biol, 2008, 613:97-106.
25. Leonard KC, Petrin D, Coupland SG, et al. XIAP protection of photoreceptors in animal models of retinitis pigmentosa[J/OL].PLoS One, 2007, 2:314[2007-03-21].http://dx.plos.org/10.1371/journal.pone.0000314.
26. Comitato A, Sanges D1, Rossi A, et al. Activation of Bax in three models of retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2014, 55:3555-3562.
27. Nir I, Kedzierski W, Chen J, et al. Expression of Bcl-2 protects against photoreceptor degeneration in retinal degeneration slow (rds) mice[J].J Neurosci, 2000, 20:2150-2154.
28. Tsang SH, Chen J, Kjeldbye H, et al. Retarding photoreceptor degeneration in Pdegtm1/Pdegtml mice by an apoptosis suppressor gene[J]. Invest Ophthalmol Vis Sci, 1997, 38:943-950.
29. Cayouette M, Behn D, Sendtner M, et al. Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse[J]. J Neurosci, 1998, 18:9282-9293.
30. Liang FQ, Aleman TS, Dejneka NS, et al. Long-term protection of retinal structure but not function using RAAV CNTF in animal models of retinitis pigmentosa[J]. Mol Ther, 2001, 4:461-472.
31. Bok D, Yasumura D, Matthes MT, et al.Effects of adeno-associated virus-vectored ciliary neurotrophic factor on retinal structure and function in mice with a P216L rds/peripherin mutation[J]. Exp Res, 2002, 74:719-735.
32. Rhee KD, Ruiz A, Duncan JL, et al.Molecular and cellular alterations induced by sustained expression of ciliary neurotrophic factor in a mouse model of retinitis pigmentosa[J]. Invest Ophthalmol Vis Sci, 2007, 48:1389-1400.
33. McGee Sanftner LH, Abel H, Hauswirth WW, et al.Glial cell line derived neurotrophic factor delays photoreceptor degeneration in a transgenic rat model of retinitis pigmentosa[J].Mol Ther, 2001, 4:622-629.
34. Lawrence JM, Keegan DJ, Muir EM, et al.Transplantation of Schwann cell line clones secreting GDNF or BDNF into the retinas of dystrophic Royal College of Surgeons rats[J].Invest Ophthalmol Vis Sci, 2004, 45:267-274.
35. Andrieu-Soler C, Aubert-Pouessel A, Doat M, et al. Intravitreous injection of PLGA micrespheres encapsulating GDNF promotes the survival of photoreceptors in the rd1/rd1 mouse[J].Mol Vis, 2005, 11:1002-1011.
36. Buch PK, MacLaren RE, 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[J]. Mol Ther, 2006, 14:700-709.
37. Lau D, McGee LH, Zhou S, et al.Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2[J].Invest Ophthalmol Vis Sci, 2000, 41:3622-3633.
38. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis[J]. N Engl J Med, 2008, 358:2231-2239.
39. Cideciyan AV, Hauswirth WW, Aleman TS, et al. Vision 1 year after gene therapy for Leber's congenital amaurosis[J]. N Engl J Med, 2009, 361:725-727.
40. Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18:643-650.
41. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis:a phase 1 dose-escalation trial[J]. Lancet, 2009, 374:1597-1605.
42. Cideciyan AV, Hauswirth WW, Aleman TS, et al. Human RPE65 gene therapy for Leber congenital amaurosis:persistence of early visual improvements and safety at 1 year[J]. Hum Gene Ther, 2009, 20:999-1004.
43. Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18:643-650.

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腺相关病毒载体在视网膜色素变性基因治疗中的应用研究进展

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