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2023年7月 第38卷 第7期11
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ABCA4 相关 Stargardt 病基因治疗的研究进展

Research progress on gene therapy for ABCA4-related stargardt disease

来源期刊: 眼科学报 | - 发布时间:2024-07-28 收稿时间:2024/9/19 10:13:26 阅读量:18
作者:
关键词:
Stargardt病ABCA4基因基因治疗 综述
Stargardt disease ABCA4 gene gene therapy review
DOI:
10.12419/24071005
收稿时间:
2024-06-03 
修订日期:
2024-06-23 
接收日期:
2024-07-12 
Stargardt病(STGD1,OMIM#248200)是最常见的遗传性黄斑营养不良,是由ABCA4基因突变引起的常染色体隐性遗传病。该病通常在儿童晚期或成年早期发病,导致视力进行性、不可逆地损害。近年研究者在STGD1临床和分子特征以及潜在的病理生理学方面取得的重大进展,促成了许多已完成的、正在进行的和计划中的新疗法的人体临床试验。文章聚焦于STGD1的基因治疗研究进展。STGD1基因治疗的主要障碍是ABCA4基因序列过长以及ABCA4基因在光感受器细胞中的特异性转导效率不高。解决这一问题的关键是研究出具有大运载量和能高效将ABCA4基因转导进光感受器细胞的载体。目前STGD1的基因治疗策略主要包括腺相关病毒(adeno-associated viral, AAV)载体、慢病毒载体、纳米颗粒、光遗传学和反义寡核苷酸等。随着研究的深入,未来有望开发出针对STGD1的有效基因治疗方法,为患者带来新的治疗希望。该综述为临床应用和科学研究提供了宝贵的参考和思路。
Stargardt disease (STGD1, OMIM#248200) is the most common hereditary macular dystrophy, caused by mutations in the ABCA4 gene, and is an autosomal recessive inherited disorder. The disease typically manifests in late childhood or early adulthood, leading to progressive and irreversible visual impairment. Significant advances in understanding the clinical and molecular characteristics, as well as the underlying pathophysiology, have ultimately facilitated numerous human clinical trials of new therapies that have been completed, are ongoing, and are planned. This review focuses on the progress in gene therapy research for STGD1. The primary obstacle in STGD1 gene therapy is the lengthy sequence of the ABCA4 gene and the low efficiency of specific transduction of the ABCA4 gene into photoreceptor cells. The key to addressing this issue is to develop a vector with a large carrying capacity that can efficiently transduce the ABCA4 gene into photoreceptor cells. Current gene therapy strategies for STGD1 mainly include adeno-associated viral (AAV) vectors, lentiviral vectors, nanoparticles, optogenetics, and antisense oligonucleotides(AONs). With the deepening of research, it is hoped that effective gene therapy methods for STGD1 will be developed in the future, bringing new therapeutic hope to patients. This review provides valuable references and ideas for clinical applications and scientific research.

文章亮点

1. 关键发现

• 总结了目前已知的针对 STGD1 基因治疗的研究新进展,包括已经或正在进行的临床试验以及临床前研究,以期为STGD1 的治疗提供新思路。

2. 已知与发现

• 当前基因治疗策略包括腺相关病毒载体 (AAV)、慢病毒载体、纳米颗粒、光遗传学和反义寡核苷酸等方法。研究的关键在于开发能够高效将 ABCA4 基因转导入光感受器细胞的大运载量载体。随着研究的深入,未来有望开发出针对 STGD1 的有效基因治疗方法,为患者带来新的治疗希望。

3. 意义与改变

• 随着对 STGD1 研究的不断深化,未来可能会开发出有效的基因治疗策略,为患者提供新的更精准的治疗选择。本综述为临床实践和科学探索提供了重要的参考和启发。
       
       Stargardt病(STGD1, OMIM#248200)是青少年最常见的遗传性黄斑营养不良疾病,发病率为1/10 000~1/8 000[1-2],由Dr.Karl Stargardt等于1909年首次报道而命[3]。STGD1通常于儿童晚期或成年早期或中期起病,可导致进行性、不可逆的视力损害。STGD1与ABCA4基因的致病遗传变异有关,遗传方式为常染色体隐性遗传。尽管STGD1目前尚无有效的治疗方法,但有多条干预途径正在研究中,包括基因治疗、药物治疗、干细胞移植等。数十项临床试验以及一些尚未投入临床试验的临床前研究正在进行。其中,基因治疗作为一种有前景的治疗策略,通过将健康的基因引入目标细胞中,以恢复其正常功能,显示出了治疗单基因遗传性眼病的潜力。本综述评估已经研究或正在研究的STGD1基因治疗进展,旨在为临床应用和科学研究提供新思路。

1 STGD1的分子遗传学

1.1 ABCA4基因

       ABCA4基因定位于人类染色体1p22.1[4],由50个外显子组成,基因组DNA全长128 kb,开放阅读区长6 819个碱基对,其编码的ABCA4蛋白含2 273个氨基[5],分子量约250 kDa,位于视杆细胞和视锥细胞外节盘缘[6],ABCA4蛋白作为脂质内向翻转酶参与11-顺-视黄醛在视觉循环中的转运[7]。ABCA4有巨大的等位基因异质性,迄今为止已报道的序列变异数超过4 000,这种高度异质性给基因型表型关系的建立造成了极大的困难,预期会影响剪切或者引入终止密码子的突变为无效突变,通常与疾病的早发有关,并常表现为更严重且迅速进展的表型,伴有更广泛的视网膜受累[8-9]

1.2 STGD1致病的分子机制

       ABCA4 蛋白是 ATP 结合盒(ATP-binding cassette, ABC)转运蛋白超家族的成员,位于视杆细胞和视锥细胞的外节盘膜中。它将 N-视黄亚基-磷脂酰乙醇胺(N-retinylidene-phosphatidylethanolamine, NrPE)(视黄醛和磷脂酰乙醇胺的 Schiff 碱加合物)从管腔侧翻转到光感受器膜盘的细胞质侧[10],从而确保过量的11-顺式视黄醛从光感受器细胞中有效清除,防止有毒脂褐素化合物的积累。当ABCA4基因突变导致ABCA4蛋白缺陷时,NrPE和全反式视黄醛在光感受器膜盘内积累,膜盘被视网膜色素上皮细胞RPE吞噬后最终生成不能被代谢的N-亚视黄基-N-视黄醇胺(N-Retinylidene-N-retinylethanolamine, A2E)[11]。A2E会聚集在RPE细胞中形成脂褐质,脂褐质能够引起RPE细胞的破坏与萎[12-13],继发光感受器细胞的功能障碍及死亡,从而引发STGD1[14]。脂褐素和双视黄素化合物的积累是STGD1 的特征之一。

2 STGD1的基因治疗

2.1 概述

       基因治疗在治疗单基因遗传性视网膜病领域具有巨大的潜力。STGD1基因治疗的基本目标是将ABCA4基因传递给视网膜靶细胞,使ABCA4蛋白得以正常表达,从而减少RPE细胞中有毒脂褐素物质的积聚。STGD1基因治疗的主要障碍是ABCA4基因序列过长(6.8 kb)以及ABCA4基因在光感受器细胞中的特异性表[15]。解决这一问题的关键是研究出具有大运载量和能够高效将ABCA4基因转导进光感受器细胞的载体。大多数能够接受大运载量的载体,如慢病毒和非病毒载体,将ABCA4基因转导入光感受器细胞的效率不足,而能够有效转导光感受器细胞的载体,如腺相关病毒(AAV)的运载能力又有限。针对载体的研究取得的进展为治疗STGD1提供了未来可能的解决方案,但仍需进一步验证,以确保其安全性和有效性。

2.2 腺相关病毒载体

       腺相关病毒(adeno-associated viral, AAV)载体免疫原性低、安全性高、转导效率高且长效[16],是基因治疗的一种理想工具,在现有的基因转运载体中,基于AAV的载体在单次视网膜下给药的长期治疗中对光感受器和视网膜色素上皮RPE的靶向效率最高[17-18]。然而,其有效荷载仅4.7 kb,无法包装6.8 kb的ABCA4大编码序列,这限制了其在STGD1治疗中的应用[19]
       
为了克服这种限制,研究人员研发出双AAV载体策略(将大序列片段化后分装至2个AAV载体,而后在宿主细胞内再整合重建成大基因),并已应用于ABCA4基因。Colella等[20]和Trapani等[21]分别利用双AAV载体系统在小鼠和猪模型中实现了ABCA4基因的有效传递,并观察到一定的治疗效果。
       目前,基因组水平的双AAV载体表达策略根据不同机制大致可分为重叠(overlapping)、反式剪切(trans-splicing)以及混合(hybrid)三种类型。三种双AAV载体策略均成功地在ABCA4基因敲除小鼠模型中实现了全长ABCA4的表达,并通过减少双维A酸/A2E/脂褐质的积累提供了有效性的证据[20,22-23]
       然而,使用双AAV载体在光感受器中实现转基因表达的效率远低于使用单AAV载体,而且所有双AAV载体系统均携带部分研究者不希望表达出的副产物,这种风险在重叠、反式剪切和混合ABCA4双AAV载体中均很明显,可能会对治疗的安全性造成影响,应在临床试验前进行仔细评估。
       近期,Riedmayr等[24]提出了一种基于mRNA反式剪接重组的双AAV载体技术(reconstitution via mRNA transsplicing, REVeRT ) 并在STGD1的小鼠模型中经玻璃体腔注射后重建出全长ABCA4。REVeRT技术不仅实现了目的基因的高表达,而且避免了外来蛋白的副产的产生,降低了潜在的免疫原性风险。

2.3 慢病毒Lentivirus载体

       慢病毒载体,特别是基于马传染性贫血病毒(equine infectious anemia virus, EIAV)的载体StarGen,因其能够携带大容量的基因插入物并实现长期基因表达,而成为STGD1基因治疗的理想选择[25-26]。早期的动物研究表明,EIAV载体能够有效地将ABCA4基因传递至视网膜光感受器细胞和RPE细胞,并显著减少脂褐素A2E的积累[25]。在Abca4−/−小鼠模型中,单次视网膜下注射EIAV-ABCA4载体能够在2个月内观察到ABCA4蛋白的表达,并在1年后保持A2E水平接近正常小鼠,此外,StarGen慢病毒载体在兔和猕猴的视网膜下注射中显示出良好的安全性、耐受性和定位[26]
       基于上述研究结果,StarGen基因补充疗法(EIAV-ABCA4, SAR422459)的Ⅰ/Ⅱa期临床试验(NCT01367444)已提前终止,正在进行更长期的随访研究[27],但仍缺乏改善视力的确切证据。在安全性上,EIAV-ABCA4视网膜下注射治疗耐受性良好,仅1例出现高眼压,未发现与治疗有关的有临床意义的视功能变化。在最高剂量组的一只治疗眼中,黄斑上沉着的斑点明显减少。然而,27 %的治疗眼在眼底自发荧光(fundus autofluorescence, FAF)上表现出RPE萎缩的加重。为了全面评价EIAV-ABCA4的安全性和有效性,还需要对更多的患者进行随访和继续研究[28]

2.4 纳米颗粒

       考虑到病毒载体传递方法的局限性,纳米颗粒为更大的转基因提供了另一种载体。病毒载体可能引发免疫应答[29],但人工纳米颗粒不仅不会出现这种反应,而且没有基因大小的限制,也不整合入宿主基因组,减少了插入突变的风险。(1-氨基乙基)亚氨基双[N (油酰基半胱氨酸-1-氨基乙基)丙酰胺](ECO)是一种多功能pH敏感的氨基脂质,它可与任何大小的核酸自组装形成稳定的纳米颗粒制剂,而不需要辅助脂质。在纳米颗粒被细胞内吞后,ECO促进pH敏感的两亲性内体从纳米颗粒中逃逸,引起治疗基因的有效胞内递送[30-32]
       研究人员设计出ECO/pRHO-ABCA4纳米颗粒[31],该纳米粒携带含有ABCA4全长编码序列的牛视紫红质(rhodopsin, RHO)启动子的紧凑质粒DNA,通过自组装的形式,能够在视网膜光感受器细胞中特异性表达ABCA4基因。研究表明,ECO/pRHO-ABCA4纳米颗粒在ABCA4−/−小鼠模型中能够显著减少A2E的积累,延缓Stargardt病的进展[31-32],为了进一步增强基因表达,研究者在ABCA4质粒中引入了SV40增强子。体外实验表明,带有SV40增强子的纳米颗粒在人视网膜色素上皮细胞ARPE-19细胞中能够显著提高ABCA4 mRNA表达水平[32]。然而,在ABCA4−/−小鼠模型中的体内实验结果显示,带有SV40增强子的纳米颗粒并未表现出优于未修饰质粒的治疗效果,可能是由于SV40增强子在不同细胞类型中的表现差异[32]。在视网膜基因治疗中,含有AT富集区的支架/基质附着区(scaffold/matrixattachment region, S/MAR)可以增强持续的长期基因表达。研究者构建了带有可以驱动基因在光感受器中的特异性表达的G蛋白偶联受体激酶1(G protein-coupled receptor kinase 1, GRK1)启动子和人类来源的S/MAR增强子的纳米颗粒制剂,该纳米颗粒可以诱导ABCA4蛋白在光感受器中特异性表达。重复视网膜下注射导致ABCA4表达延长和治疗效果增强,并显著抑制A2E积累,从而有效治疗STGD1。该纳米颗粒在小鼠体内多次视网膜下注射中表现出良好的安全性,没有明显的不良反应和免疫原性[33]

2.5 光遗传学

       光遗传学是一种针对晚期疾病的基因治疗方法,使用腺相关病毒载体AAV通过玻璃体腔注射的方式使残留的非光感受器细胞对光敏感。多特征性视蛋白-Ⅰ(multicharacteristic opsin-I, MCO-Ⅰ)基因编码光敏感离子通道,该载体导致双极细胞中视蛋白的表达。当受到环境光照射时,它会导致双极细胞的去极化,使其对环境光敏感。在视网膜变性的动物模型中使用AAV装载的MCO-Ⅰ(vMCO-Ⅰ),MCO-Ⅰ被可靠地传递到特定的视网膜细胞,显著改善了使用放射臂水迷宫的动物视觉引导行为[34]
       正在进行的一项多中心开放性Ⅱ期临床试验(STARLIGHT, NCT05417126)正在评估6例因Stargardt病出现晚期视力丧失的患者单次玻璃体腔注射vMCO-010的安全性和有效性。初步结果显示,vMCO-010治疗的患者在最佳矫正视力(BCVA)方面显示出有临床意义的改善,Octopus视野计测得平均视野增益为3 dB,且未出现严重的不良事件[35]

2.6 反义寡核苷酸

       STGD1致病变异中有大量的内含子变异,改变了mRNA前体的剪接过程而致病。反义寡核苷酸(antisense oligonucleotide, AON) 是作为 RNA 调节剂的人工核苷酸的单链小片段[36]。它们与mRNA或pre-mRNA的互补核苷酸结合,从而通过防止深层内含子过早剪接位点的剪接或强制外显子跳跃以防止产生有毒蛋白质,从而有望治疗由深层内含子变异引起的STGD1。Kaltak等[37-38]针对最常见的严重ABCA4变异体c.5461-10T>C设计出QR–1011(一种AON)。该突变导致外显子39或外显子39和40的跳跃,产生移码突变。研究发现,QR-1011能够显著增加正确剪接的mRNA比例,并在患者来源的视网膜类器官中恢复ABCA4蛋白的表达。AON在c.769-784C>T、c.5196+1137G>A等多种ABCA4深层内含子变异中也有类似修复效果[39-40]
       有研究者使用单个U7snRNA载体向多个基因位点递送反义寡核苷酸(AON)修复ABCA4基因剪接缺陷,在人胚肾细胞HEK293T中发现,多重U7snRNA载体能够显著修复所有测试的剪接缺陷,但在患者来源的光感受器前体细胞(photoreceptor precursor cell, PPC)测试中尽管表达了U7snRNA基因却并未实现显著的剪接校正[41]
       研究人员针对一名10岁女童的c.6817-713A>G变异设计了AON,并在HEK293T细胞、患者来源的成纤维细胞和PPC中测试AON的剪接纠正效果,发现AON在这三种细胞中显著减少了伪外显子的插入,有效地纠正了变异引起的剪接缺陷,显示出对剪接错误的修复能力[42]。这是首例针对一个极罕见的STGD1病例的个性化AON方法的临床前测试,为个性化治疗STGD1提供了潜在的解决方案,但仍需进行深入的验证工作,以验证最小的安全风险及其可能给患者带来的潜在益处。

3 总结与展望

       STGD1目前尚无明确的治疗方法,一旦确诊就会造成进行性的、不可逆的视力损害甚至失明。基因治疗在单基因遗传性视网膜病领域具有巨大的潜力,本综述讨论了一些潜在的基因治疗策略与目前正在进行的一些临床试验。随着各项研究的深入和临床试验的推进,未来有望出现对 STGD1的有效基因治疗。

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1、Michaelides M, Hunt DM, Moore AT. The genetics of inherited macular dystrophies[ J]. J Med Genet, 2003, 40(9): 641-650. DOI: 10.1136/ jmg.40.9.641.Michaelides M, Hunt DM, Moore AT. The genetics of inherited macular dystrophies[ J]. J Med Genet, 2003, 40(9): 641-650. DOI: 10.1136/ jmg.40.9.641.
2、Fujinami K, Lois N, Mukherjee R , et al. A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations[ J]. Invest Ophthalmol Vis Sci, 2013, 54(13): 8181-8190. DOI: 10.1167/iovs.13-12104.Fujinami K, Lois N, Mukherjee R , et al. A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations[ J]. Invest Ophthalmol Vis Sci, 2013, 54(13): 8181-8190. DOI: 10.1167/iovs.13-12104.
3、Stargardt%20K%20.%20%C3%9Cber%20famili%C3%A4re%2C%20progressive%20Degeneration%20in%20der%20%0AMaculagegend%20des%20Auges%5B%20J%5D.%20Albrecht%20Von%20Graefes%20Arch%20F%C3%BCr%20%0AOphthalmol%2C%201909%2C%2071(3)%3A%20534-550.%20DOI%3A%2010.1007%2FBF01961301.Stargardt%20K%20.%20%C3%9Cber%20famili%C3%A4re%2C%20progressive%20Degeneration%20in%20der%20%0AMaculagegend%20des%20Auges%5B%20J%5D.%20Albrecht%20Von%20Graefes%20Arch%20F%C3%BCr%20%0AOphthalmol%2C%201909%2C%2071(3)%3A%20534-550.%20DOI%3A%2010.1007%2FBF01961301.
4、Kaplan J, Gerber S, Larget-Piet D, et al. A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1[ J]. Nat Genet, 1993, 5(3): 308-311. DOI: 10.1038/ng1193-308.Kaplan J, Gerber S, Larget-Piet D, et al. A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1[ J]. Nat Genet, 1993, 5(3): 308-311. DOI: 10.1038/ng1193-308.
5、Allikmets R. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy[ J]. Nat Genet, 1997, 17(1): 122. DOI: 10.1038/ng0997-122a.Allikmets R. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy[ J]. Nat Genet, 1997, 17(1): 122. DOI: 10.1038/ng0997-122a.
6、Illing M, Molday LL, Molday RS. The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily[ J]. J Biol Chem, 1997, 272(15): 10303-10310. DOI: 10.1074/jbc.272.15.10303.Illing M, Molday LL, Molday RS. The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily[ J]. J Biol Chem, 1997, 272(15): 10303-10310. DOI: 10.1074/jbc.272.15.10303.
7、Quazi F, Lenevich S, Molday RS. ABCA4 is an N-retinylidenephosphatidy lethanolamine and phosphatidy lethanolamine importer[ J]. Nat Commun, 2012, 3: 925. DOI: 10.1038/ncomms1927.Quazi F, Lenevich S, Molday RS. ABCA4 is an N-retinylidenephosphatidy lethanolamine and phosphatidy lethanolamine importer[ J]. Nat Commun, 2012, 3: 925. DOI: 10.1038/ncomms1927.
8、Fujinami K , Lois N, Davidson AE, et al. A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations[ J]. Am J Ophthalmol, 2013, 155(6): 1075-1088.e13. DOI: 10.1016/j.ajo.2013.01.018.Fujinami K , Lois N, Davidson AE, et al. A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations[ J]. Am J Ophthalmol, 2013, 155(6): 1075-1088.e13. DOI: 10.1016/j.ajo.2013.01.018.
9、Zernant J, Schubert C, Im KM, et al. Analysis of the ABCA4 gene by next-generation sequencing[ J]. Invest Ophthalmol Vis Sci, 2011, 52(11): 8479-8487. DOI: 10.1167/iovs.11-8182.Zernant J, Schubert C, Im KM, et al. Analysis of the ABCA4 gene by next-generation sequencing[ J]. Invest Ophthalmol Vis Sci, 2011, 52(11): 8479-8487. DOI: 10.1167/iovs.11-8182.
10、Molday RS, Garces FA, Scortecci JF, et al. Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration[ J]. Prog Retin Eye Res, 2022, 89: 101036. DOI: 10.1016/j.preteyeres.2021.101036.Molday RS, Garces FA, Scortecci JF, et al. Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration[ J]. Prog Retin Eye Res, 2022, 89: 101036. DOI: 10.1016/j.preteyeres.2021.101036.
11、Sparrow JR , Kim SR , Cuervo AM, et al. A2E, a pigment of RPE lipofuscin, is generated from the precursor, A2PE by a lysosomal enzyme activity[ J]. Adv Exp Med Biol, 2008, 613: 393-398. DOI: 10.1007/978-0-387-74904-4_46.Sparrow JR , Kim SR , Cuervo AM, et al. A2E, a pigment of RPE lipofuscin, is generated from the precursor, A2PE by a lysosomal enzyme activity[ J]. Adv Exp Med Biol, 2008, 613: 393-398. DOI: 10.1007/978-0-387-74904-4_46.
12、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.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.
13、Sparrow JR , Boulton M. RPE lipofuscin and its role in retinal pathobiology[ J]. Exp Eye Res, 2005, 80(5): 595-606. DOI: 10.1016/ j.exer.2005.01.007.Sparrow JR , Boulton M. RPE lipofuscin and its role in retinal pathobiology[ J]. Exp Eye Res, 2005, 80(5): 595-606. DOI: 10.1016/ j.exer.2005.01.007.
14、方艳文, 张勇进. Stargardt病的病因及治疗展望[ J]. 国外医 学(眼科学分册), 2003, 27(5): 306-309. DOI: 10.3760/cma. j.issn.1673-5803.2003.05.013.
Fang YW, Zhang YJ. Etiology and treatment prospect of Stargardt's disease[ J]. Int Rev Ophthalmol, 2003, 27(5): 306-309. DOI: 10.3760/ cma.j.issn.1673-5803.2003.05.013.
Fang YW, Zhang YJ. Etiology and treatment prospect of Stargardt's disease[ J]. Int Rev Ophthalmol, 2003, 27(5): 306-309. DOI: 10.3760/ cma.j.issn.1673-5803.2003.05.013.
15、Piotter E, McClements ME, MacLaren RE. The scope of pathogenic ABCA4 mutations targetable by CRISPR DNA base editing systems-a systematic review[ J]. Front Genet, 2021, 12: 814131. DOI: 10.3389/ fgene.2021.814131.Piotter E, McClements ME, MacLaren RE. The scope of pathogenic ABCA4 mutations targetable by CRISPR DNA base editing systems-a systematic review[ J]. Front Genet, 2021, 12: 814131. DOI: 10.3389/ fgene.2021.814131.
16、Colella P, Auricchio A. Gene therapy of inherited retinopathies: a long and successful road from viral vectors to patients[ J]. Hum Gene Ther, 2012, 23(8): 796-807. DOI: 10.1089/hum.2012.123.Colella P, Auricchio A. Gene therapy of inherited retinopathies: a long and successful road from viral vectors to patients[ J]. Hum Gene Ther, 2012, 23(8): 796-807. DOI: 10.1089/hum.2012.123.
17、Colella P, Cotugno G, Auricchio A. Ocular gene therapy: current progress and future prospects[ J]. Trends Mol Med, 2009, 15(1): 23- 31. DOI: 10.1016/j.molmed.2008.11.003.Colella P, Cotugno G, Auricchio A. Ocular gene therapy: current progress and future prospects[ J]. Trends Mol Med, 2009, 15(1): 23- 31. DOI: 10.1016/j.molmed.2008.11.003.
18、Vandenberghe LH, Auricchio A. Novel adeno-associated viral vectors for retinal gene therapy[ J]. Gene Ther, 2012, 19(2): 162-168. DOI: 10.1038/gt.2011.151.Vandenberghe LH, Auricchio A. Novel adeno-associated viral vectors for retinal gene therapy[ J]. Gene Ther, 2012, 19(2): 162-168. DOI: 10.1038/gt.2011.151.
19、Hermonat PL, Quirk JG, Bishop BM, et al. The packaging capacity of adeno-associated virus (AAV) and the potential for wild-type-plus AAV gene therapy vectors[ J]. FEBS Lett, 1997, 407(1): 78-84. DOI: 10.1016/s0014-5793(97)00311-6.Hermonat PL, Quirk JG, Bishop BM, et al. The packaging capacity of adeno-associated virus (AAV) and the potential for wild-type-plus AAV gene therapy vectors[ J]. FEBS Lett, 1997, 407(1): 78-84. DOI: 10.1016/s0014-5793(97)00311-6.
20、Colella P, Trapani I, Cesi G, et al. Efficient gene delivery to the coneenriched pig retina by dual AAV vectors[ J]. Gene Ther, 2014, 21(4): 450-456. DOI: 10.1038/gt.2014.8.Colella P, Trapani I, Cesi G, et al. Efficient gene delivery to the coneenriched pig retina by dual AAV vectors[ J]. Gene Ther, 2014, 21(4): 450-456. DOI: 10.1038/gt.2014.8.
21、Trapani I, Toriello E, de Simone S, et al. Improved dual AAV vectors with reduced expression of truncated proteins are safe and effective in the retina of a mouse model of Stargardt disease[ J]. Hum Mol Genet, 2015, 24(23): 6811-6825. DOI: 10.1093/hmg/ddv386.Trapani I, Toriello E, de Simone S, et al. Improved dual AAV vectors with reduced expression of truncated proteins are safe and effective in the retina of a mouse model of Stargardt disease[ J]. Hum Mol Genet, 2015, 24(23): 6811-6825. DOI: 10.1093/hmg/ddv386.
22、Dyka FM, Molday LL, Chiodo VA, et al. Dual ABCA4-AAV vector treatment reduces pathogenic retinal A2E accumulation in a mouse model of autosomal recessive stargardt disease[ J]. Hum Gene Ther, 2019, 30(11): 1361-1370. DOI: 10.1089/hum.2019.132.Dyka FM, Molday LL, Chiodo VA, et al. Dual ABCA4-AAV vector treatment reduces pathogenic retinal A2E accumulation in a mouse model of autosomal recessive stargardt disease[ J]. Hum Gene Ther, 2019, 30(11): 1361-1370. DOI: 10.1089/hum.2019.132.
23、McClements ME, Barnard AR, Singh MS, et al. An AAV dual vector strategy ameliorates the stargardt phenotype in adult Abca4-/- mice[ J]. Hum Gene Ther, 2019, 30(5): 590-600. DOI: 10.1089/hum.2018.156.McClements ME, Barnard AR, Singh MS, et al. An AAV dual vector strategy ameliorates the stargardt phenotype in adult Abca4-/- mice[ J]. Hum Gene Ther, 2019, 30(5): 590-600. DOI: 10.1089/hum.2018.156.
24、Riedmayr LM, Hinrichsmeyer KS, Thalhammer SB, et al. mRNA transsplicing dual AAV vectors for (epi)genome editing and gene therapy[ J]. Nat Commun, 2023, 14(1): 6578. DOI: 10.1038/s41467-023-42386- 0.Riedmayr LM, Hinrichsmeyer KS, Thalhammer SB, et al. mRNA transsplicing dual AAV vectors for (epi)genome editing and gene therapy[ J]. Nat Commun, 2023, 14(1): 6578. DOI: 10.1038/s41467-023-42386- 0.
25、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.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.
26、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.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.
27、Tanna P, Strauss RW, Fujinami K, et al. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options[ J]. Br J Ophthalmol, 2017, 101(1): 25-30. DOI: 10.1136/ bjophthalmol-2016-308823.Tanna P, Strauss RW, Fujinami K, et al. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options[ J]. Br J Ophthalmol, 2017, 101(1): 25-30. DOI: 10.1136/ bjophthalmol-2016-308823.
28、Parker MA, Erker LR , Audo I, et al. Three-year safety results of SAR422459 (EIAV-ABCA4) gene therapy in patients with ABCA4- associated stargardt disease: an open-label dose-escalation phase I/IIa clinical trial, cohorts 1-5[ J]. Am J Ophthalmol, 2022, 240: 285-301. DOI: 10.1016/j.ajo.2022.02.013.Parker MA, Erker LR , Audo I, et al. Three-year safety results of SAR422459 (EIAV-ABCA4) gene therapy in patients with ABCA4- associated stargardt disease: an open-label dose-escalation phase I/IIa clinical trial, cohorts 1-5[ J]. Am J Ophthalmol, 2022, 240: 285-301. DOI: 10.1016/j.ajo.2022.02.013.
29、Bucher K, Rodríguez-Bocanegra E, Dauletbekov D, et al. Immune responses to retinal gene therapy using adeno-associated viral vectors - Implications for treatment success and safety[ J]. Prog Retin Eye Res, 2021, 83: 100915. DOI: 10.1016/j.preteyeres.2020.100915.Bucher K, Rodríguez-Bocanegra E, Dauletbekov D, et al. Immune responses to retinal gene therapy using adeno-associated viral vectors - Implications for treatment success and safety[ J]. Prog Retin Eye Res, 2021, 83: 100915. DOI: 10.1016/j.preteyeres.2020.100915.
30、Sun D, Sahu B, Gao S, et al. Targeted multifunctional lipid ECO plasmid DNA nanoparticles as efficient non-viral gene therapy for leber's congenital amaurosis[ J]. Mol Ther Nucleic Acids, 2017, 7: 42- 52. DOI: 10.1016/j.omtn.2017.02.005.Sun D, Sahu B, Gao S, et al. Targeted multifunctional lipid ECO plasmid DNA nanoparticles as efficient non-viral gene therapy for leber's congenital amaurosis[ J]. Mol Ther Nucleic Acids, 2017, 7: 42- 52. DOI: 10.1016/j.omtn.2017.02.005.
31、Sun D, Schur RM, Sears AE, et al. Non-viral gene therapy for stargardt disease with ECO/pRHO-ABCA4 self-assembled nanoparticles[ J]. Mol Ther, 2020, 28(1): 293-303. DOI: 10.1016/j.ymthe.2019.09.010.Sun D, Schur RM, Sears AE, et al. Non-viral gene therapy for stargardt disease with ECO/pRHO-ABCA4 self-assembled nanoparticles[ J]. Mol Ther, 2020, 28(1): 293-303. DOI: 10.1016/j.ymthe.2019.09.010.
32、Sun D, Sun W, Gao SQ, et al. Formulation and efficacy of ECO/pRHOABCA4-SV40 nanoparticles for nonviral gene therapy of Stargardt disease in a mouse model[ J]. J Control Release, 2021, 330: 329-340. DOI: 10.1016/j.jconrel.2020.12.010.Sun D, Sun W, Gao SQ, et al. Formulation and efficacy of ECO/pRHOABCA4-SV40 nanoparticles for nonviral gene therapy of Stargardt disease in a mouse model[ J]. J Control Release, 2021, 330: 329-340. DOI: 10.1016/j.jconrel.2020.12.010.
33、Sun D, Sun W, Gao SQ, et al. Effective gene therapy of Stargardt disease with PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles[ J]. Mol Ther Nucleic Acids, 2022, 29: 823-835. DOI: 10.1016/j.omtn.2022.08.026.Sun D, Sun W, Gao SQ, et al. Effective gene therapy of Stargardt disease with PEG-ECO/pGRK1-ABCA4-S/MAR nanoparticles[ J]. Mol Ther Nucleic Acids, 2022, 29: 823-835. DOI: 10.1016/j.omtn.2022.08.026.
34、Wright W, Gajjeraman S, Batabyal S, et al. Restoring v ision in mice w ith retinal degeneration using multicharacteristic opsin[ J]. Neurophotonics, 2017, 4(4): 041505. DOI: 10.1117/1. NPh.4.4.041505.Wright W, Gajjeraman S, Batabyal S, et al. Restoring v ision in mice w ith retinal degeneration using multicharacteristic opsin[ J]. Neurophotonics, 2017, 4(4): 041505. DOI: 10.1117/1. NPh.4.4.041505.
35、Therapeutics, N. Nanoscope Therapeutics Unveils Clinical Trial Results for MCO-010 in Treating Stargardt Disease. Available online: https://www.prnewswire.com/news-releases/nanoscope-therapeuticsunveils-clinical-trial-results-for-mco-010-in-treating-stargardtdisease-301896754.html (accessed on 1 September 2023).Therapeutics, N. Nanoscope Therapeutics Unveils Clinical Trial Results for MCO-010 in Treating Stargardt Disease. Available online: https://www.prnewswire.com/news-releases/nanoscope-therapeuticsunveils-clinical-trial-results-for-mco-010-in-treating-stargardtdisease-301896754.html (accessed on 1 September 2023).
36、Xue K, MacLaren RE. Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases[ J].Expert Opin Investig Drugs, 2020, 29(10): 1163-1170. DOI: 10.1080/13543784.2020.1804853.Xue K, MacLaren RE. Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases[ J].Expert Opin Investig Drugs, 2020, 29(10): 1163-1170. DOI: 10.1080/13543784.2020.1804853.
37、Kaltak M, de Bruijn P, Piccolo D, et al. Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C[ J]. Mol Ther Nucleic Acids, 2023, 31: 674-688. DOI: 10.1016/j.omtn.2023.02.020.Kaltak M, de Bruijn P, Piccolo D, et al. Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C[ J]. Mol Ther Nucleic Acids, 2023, 31: 674-688. DOI: 10.1016/j.omtn.2023.02.020.
38、Kaltak M, de Bruijn P, van Leeuwen W, et al. QR-1011 restores defective ABCA4 splicing caused by multiple severe ABCA4 variants underlying Stargardt disease[ J]. Sci Rep, 2024, 14(1): 684. DOI: 10.1038/s41598-024-51203-7.Kaltak M, de Bruijn P, van Leeuwen W, et al. QR-1011 restores defective ABCA4 splicing caused by multiple severe ABCA4 variants underlying Stargardt disease[ J]. Sci Rep, 2024, 14(1): 684. DOI: 10.1038/s41598-024-51203-7.
39、Tomkiewicz TZ, Nieuwenhuis SE, Cremers FPM, et al. Correction of the splicing defect caused by a recurrent variant in ABCA4 (c.769- 784C>T) that underlies stargardt disease[ J]. Cells, 2022, 11(24): 3947. DOI: 10.3390/cells11243947.Tomkiewicz TZ, Nieuwenhuis SE, Cremers FPM, et al. Correction of the splicing defect caused by a recurrent variant in ABCA4 (c.769- 784C>T) that underlies stargardt disease[ J]. Cells, 2022, 11(24): 3947. DOI: 10.3390/cells11243947.
40、Khan M, Arno G, Fakin A, et al. Detailed phenotyping and therapeutic strategies for intronic ABCA4 variants in stargardt disease[ J]. Mol Ther Nucleic Acids, 2020, 21: 412-427. DOI: 10.1016/j.omtn.2020.06.007.Khan M, Arno G, Fakin A, et al. Detailed phenotyping and therapeutic strategies for intronic ABCA4 variants in stargardt disease[ J]. Mol Ther Nucleic Acids, 2020, 21: 412-427. DOI: 10.1016/j.omtn.2020.06.007.
41、Suárez-Herrera N, Riswick IB, Vázquez-Domínguez I, et al. Proof-ofconcept for multiple AON delivery by a single U7snRNA vector to restore splicing defects in ABCA4[ J]. Mol Ther, 2024, 32(3): 837-851. DOI: 10.1016/j.ymthe.2024.01.019.Suárez-Herrera N, Riswick IB, Vázquez-Domínguez I, et al. Proof-ofconcept for multiple AON delivery by a single U7snRNA vector to restore splicing defects in ABCA4[ J]. Mol Ther, 2024, 32(3): 837-851. DOI: 10.1016/j.ymthe.2024.01.019.
42、Suárez-Herrera N, Li CHZ, Leijsten N, et al. Preclinical development of antisense oligonucleotides to rescue aberrant splicing caused by an ultrarare ABCA4 variant in a child with early-onset stargardt disease[ J]. Cells, 2024, 13(7): 601. DOI: 10.3390/cells13070601.Suárez-Herrera N, Li CHZ, Leijsten N, et al. Preclinical development of antisense oligonucleotides to rescue aberrant splicing caused by an ultrarare ABCA4 variant in a child with early-onset stargardt disease[ J]. Cells, 2024, 13(7): 601. DOI: 10.3390/cells13070601.
1、广州市科技计划项目(SL2022A03J00452);中山大学2023年校级本科教学质量工程项 目(教务2023-394-39);白求恩·朗沐中青年眼科科研基金(BJ-LM2021014J)。
This work was supported by the Science and Technology Program of Guangzhou, China (SL2022A03J00452), Sun Yat-sen University's 2023 University-level Undergraduate Teaching Quality Engineering Project(2023-394-39) and the Bethune?Lumitin Research Funding for the young and middle-aged Ophthalmologists, China (BJ-LM2021014J).()
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