Leber先天性黑矇Ⅱ型基因治疗进展_Chinese Journal of Ocular Fundus Diseases

Authors：

吴艺君 , 郑钦象 ,  李文生

325027 温州医科大学附属眼视光医院(吴艺君, 现在中国人民解放军第180医院眼科;李文生, 现在厦门大学附属厦门眼科中心);

Corresponding author：

李文生, Email: drlws@163.net

Keywords：

Leber先天性黑矇/治疗; 基因疗法; 临床试验; 综述

DOI：

10.3760/cma.j.issn.1005-1015.2014.05.030

Video：

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Abstract Full text Figures/Tables Video References Cited by

Leber先天性黑矇(LCA)Ⅱ型以临床表现多样化与遗传异质性为主要特点。视网膜色素上皮细胞65(RPE65)基因是唯一能进行LCAⅡ型基因治疗临床试验的靶基因,在此基础上开展的临床试验结果已显示出一定的安全性和有效性。经视网膜下腔注射携带有RPE65基因的重组腺病毒载体后,患者均未发生眼部炎症及全身系统性免疫排斥反应等严重不良反应,且其视力、视野、视网膜光敏感度、瞳孔对光反射、眼球震颤、视觉行为等均有改善。但其在如何降低基因治疗本身对视网膜结构和功能的损害等方面仍然面临诸多挑战。

Citation： 吴艺君, 郑钦象, 李文生. Leber先天性黑矇Ⅱ型基因治疗进展. Chinese Journal of Ocular Fundus Diseases, 2014, 30(5): 532-534. doi: 10.3760/cma.j.issn.1005-1015.2014.05.030 Copy

1.	den Hollander AI,Roepman R,Koenekoop RK,et al.Leber congenital amaurosis:genes, proteins and disease mechanisms[J]. Prog Retin Eye Res,2008,27:391-419.
2.	van Wijk E,Kersten FF,Kartono A,et al.Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein[J].Hum Mol Genet,2009,18:51-64.
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4.	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.
5.	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.
6.	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.
7.	Ashtari M,Cyckowski LL,Monroe JF,et al.The human visual cortex responds to gene therapy-mediated recovery of retinal function[J].J Clin Invest,2011,121:2160-2168.
8.	Bennett J,Ashtari M,Wellman J,et al.AAV2 gene therapy readministration in three adults with congenital blindness[J]. Sci Transl Med, 2012, 4:115-120.
9.	Hauswirth WW, Aleman TS, Kaushal S, 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[J]. Hum Gene Ther,2008,19:979-990.
10.	Cideciyan AV,Aleman TS,Boye SL,et al.Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics[J].Proc Natl Acad Sci USA,2008,105:15112-15117.
11.	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.
12.	Jacobson SG,Cideciyan AV,Ratnakaram R,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[J]. Arch Ophthalmol,2012,130:9-24.
13.	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.
14.	Banin E,Bandah-Rozenfeld D,Obolensky A,et al.Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population:human gene therapy initiated in Israel[J]. Hum Gene Ther, 2010, 21:1749-1757.
15.	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.
16.	NarfstrÖm K, Katz ML, Ford M, et al. In vivo gene therapy in young and adult RPE65-/-dogs produces long-term visual improvement[J]. J Hered, 2003, 94:31-37.
17.	NarfstrÖm K, Katz ML, Bragadottir R, et al. Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog[J]. Invest Ophthalmol Vis Sci, 2003, 44:1663-1672.
18.	徐玉乐,李光辉.Leber先天性黑矇致病基因研究及基因治疗进展[J].中华眼底病杂志,2011,27:499-502.

1. den Hollander AI,Roepman R,Koenekoop RK,et al.Leber congenital amaurosis:genes, proteins and disease mechanisms[J]. Prog Retin Eye Res,2008,27:391-419.
2. van Wijk E,Kersten FF,Kartono A,et al.Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein[J].Hum Mol Genet,2009,18:51-64.
3. Henderson RH,Waseem N, Searle R,et al. An assessment of the apex microarray technology in genotyping patients with Leber congenital amaurosis and early-onset severe retinal dystrophy[J]. Invest Ophthalmol Vis Sci,2007,48:5684-5689.
4. 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.
5. 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.
6. 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.
7. Ashtari M,Cyckowski LL,Monroe JF,et al.The human visual cortex responds to gene therapy-mediated recovery of retinal function[J].J Clin Invest,2011,121:2160-2168.
8. Bennett J,Ashtari M,Wellman J,et al.AAV2 gene therapy readministration in three adults with congenital blindness[J]. Sci Transl Med, 2012, 4:115-120.
9. Hauswirth WW, Aleman TS, Kaushal S, 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[J]. Hum Gene Ther,2008,19:979-990.
10. Cideciyan AV,Aleman TS,Boye SL,et al.Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics[J].Proc Natl Acad Sci USA,2008,105:15112-15117.
11. 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.
12. Jacobson SG,Cideciyan AV,Ratnakaram R,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[J]. Arch Ophthalmol,2012,130:9-24.
13. 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.
14. Banin E,Bandah-Rozenfeld D,Obolensky A,et al.Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population:human gene therapy initiated in Israel[J]. Hum Gene Ther, 2010, 21:1749-1757.
15. 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.
16. NarfstrÖm K, Katz ML, Ford M, et al. In vivo gene therapy in young and adult RPE65-/-dogs produces long-term visual improvement[J]. J Hered, 2003, 94:31-37.
17. NarfstrÖm K, Katz ML, Bragadottir R, et al. Functional and structural recovery of the retina after gene therapy in the RPE65 null mutation dog[J]. Invest Ophthalmol Vis Sci, 2003, 44:1663-1672.
18. 徐玉乐,李光辉.Leber先天性黑矇致病基因研究及基因治疗进展[J].中华眼底病杂志,2011,27:499-502.

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