来源：Ophthalmology Times对于那些正在努力解决曾经被认为“无法治愈”疾病的视网膜专家来说，基因疗法提供了广泛的可行选择。
图1。遗传性视网膜疾病影响全球约 450 万人，迄今为止已发现 300 多种疾病基因疗法改变了我们看待以前“无法治愈”疾病的方式。我们已经看到基因治疗领域取得了惊人的进步，特别是在视网膜护理方面。遗传性视网膜疾病至少由一个基因突变引起。迄今为止已发现 300 多种疾病，遗传性视网膜疾病影响着全世界约 450 万人（图 1）。【1】在这种治疗方法中，修复基因有两大类：替换或抑制。在替代方面，我们针对的是基因特异性疾病，如Leber先天性黑内障(LCA)或x连锁色素性视网膜炎(XLRP)。在抑制中，我们抑制显性编码片段的异常功能，例如常染色体显性色素性视网膜炎（ADRP）。
表格对比了腺病毒和慢病毒的基因传递方法
另一个考虑因素是基因的传递（图2）【2】，有两种病毒可供选择：腺病毒和慢病毒。医生必须考虑两种给药方法的潜在结果，以及哪种方法最适合患者。
针对遗传性区域疾病的基因治疗的当前临床试验的管道概述
在类似的过程中，医生必须在当前可用的注射模式之间进行选择（图 3）【1】。视网膜下注射是最常见的方法。治疗剂被注入视网膜下腔，这需要引起一个小的视网膜脱离。这使得基因可以直接传递到受影响细胞（视网膜色素上皮细胞和光感受器）的部位。实际上，玻璃体内注射是一种更简单的基因传递方法。载体被注射到玻璃体中，并且必须到达目标细胞群，但大多数情况下，影响到的是视网膜内层而不是RPE细胞。这种注射方法有可能产生更强的免疫反应。目前有超过 436 项眼部基因疗法研究。对于那些正在努力解决曾经被认为“无法治愈”疾病的视网膜专家来说，这提供了广泛的可行选择。以下是可受益于基因治疗方法的视网膜疾病，以及当前正在进行的临床试验的简要概述。色素性视网膜炎
视网膜色素变性 (RP) 【3】的影响每 4000 人中就有一人受到，其中 15% 患有 XLRP。RP 造成的视杆细胞损伤会导致周边视力丧失和夜盲症。最常受影响的基因包括RHO、USH2A和RPGR；已鉴定出其他 87 个基因。遗传性 RP 与 Bardet-Biedl 和 Usher 综合征等疾病有关。基因试验：· MeiraGTx/杨森：· 1/2期试验（NCT03252847）比较不同剂量（低、中、高）视网膜下注射与XLRP患者的情况。· LUMEOUS 3 期 (NCT04671433) 目前正在进行中。· AGTC/信标疗法：· XLRP 1/2 期 SKYLINE (NCT03316560)· 目前正在进行低/高剂量 AGTC0501 视网膜下给药的 2/3 期研究 VISTA (NCT04850118)。· ProQR 疗法：· 反义寡核苷酸· ADRP 的 1/2 期试验 (NCT04123626)· 针对 Usher 综合征的 1/2 期试验 STELLAR (NCT05176717)脉络膜症
无脉络膜症是一种 X 连锁视网膜疾病，影响男性（五万分之一）；这种遗传病也有女性携带者。症状包括夜盲症（暗适应能力差）、视网膜色素上皮脱落、视野暗点（环）和眩光。黄斑可以保存到一定年龄以后。视网膜电图显示视杆细胞和视锥细胞变性。基因试验：· 4D分子治疗· CHM基因突变的1/2期试验（NCT04483440）；R100载体玻璃体内递送莱伯先天性黑蒙
莱伯先天性黑蒙是一种常染色体隐性遗传病。这种遗传性疾病很罕见，每 10 万人中只有两到三人患有这种疾病。其特征是视力为 20/200 或更差、畏光、眼球震颤和瞳孔呆滞。它与圆锥角膜、发育迟缓、嗅觉功能障碍和刻板运动有关。基因试验：· 火花疗法：· Vortigene Neparvovec (Luxturna)· FDA 批准的首个针对RPE65双等位基因突变的基因疗法· 在第 3 阶段，患者必须通过障碍路线（多亮度移动测试）。· 接受治疗的患者视网膜敏感性和视野得到改善，并且能够通过多亮度移动性测试。· 接受治疗的患者视力没有改善，中心凹变薄。· 编辑医学（Editas Medicine）：· CRISPR/Cas9· 消除CEP290基因中的点突变· ProQR 疗法：· 防止CEP290异常剪接的RNA反义寡核苷酸· 1/2 期临床试验显示视力有所改善· 阿特塞纳疗法：· 1/2 期剂量递增研究GUCY2D相关 LCA· 进行中斯塔加特病
Stargardt 病是一种典型的常染色体隐性遗传疾病。然而，与这种疾病相关的显性基因确实存在。脂肪组织堆积在黄斑上，虽然视力丧失可能从儿童时期开始，但有些患者直到成年才出现视力下降。这种疾病很罕见（万分之一），由ABCA4基因突变引起，该基因会清除光感受器中的脂褐质成分 A2E。视力通常可以保持，但可能会恶化至 20/400。基因试验：· 赛诺菲· 1/2a 期研究：SAR422459· 进行中· 阿尔克斯（Alkeus）· 吉尔德尿黄醇（Gildeuretinol） (ALK-001)色盲色盲影响所有 3 种视锥细胞光感受器。患者可能出现视力差、畏光、眼球震颤以及部分或全部色盲等症状。基因试验：· MeiraGTx/杨森· AAV-CNGB3 在成人和儿童患者中的 1/2 期试验· AAV-CNGA3 在儿科患者（3-15 岁）中的 1/2 期试验· 应用基因技术公司 (AGTC)· CNGA3和CNGB3突变的1/2期临床试验参考1.达尔卡拉·D，萨赫勒·JA。遗传性视网膜变性的基因治疗。CR 生物。2014 年 3 月；337(3)：185-92。doi：10.1016/j.crvi.2014.01.002。电子版 2014 年 3 月 11 日。PMID：24702845。2.卡尔 ME，托尔特拉 BJ。血友病的新兴和未来疗法。J血液医学。2015 年 9 月 3 日；6:245-55。doi：10.2147/JBM.S42669。电话号码：26366108；PMCID：PMC4562652。3.脉络膜眼底拼贴图像。MacDonald IM、Hume S、Zhai Y 等。无脉络膜血症。2003 年 2 月 21 日 [2021 年 3 月 4 日更新]。见：Adam MP、Mirzaa GM、Pagon RA 等人，编辑。GeneReviews® [互联网]。西雅图（华盛顿州）：华盛顿大学西雅图分校；1993-2023。可从：https://www.ncbi.nlm.nih.gov/books/NBK1337/Inherited retinal diseases and gene therapies: A pharmaceutical overviewFor retinal specialists grappling with diseases once thought “untreatable,” gene therapies present a wide range of viable optionsFigure 1. Inherited retinal conditions affect approximately 4.5 million people worldwide, and more than 300 diseases have been identified so far1Gene therapy has changed the way we look at diseases that were previously “untreatable.” We have seen amazing advances in the gene therapy category, especially in retina care. Inherited retinal disease is caused by at least a single gene mutation. With more than 300 diseases identified so far, inherited retinal conditions affect approximately 4.5 million people worldwide (Figure 1).1A table contrasts adenovirus and lentivirus gene delivery methodsWithin this therapeutic approach, there are two broad categories for repairing genes: replacement or suppression. In replacement, we are gene-specific in diseases such as Leber congenital amaurosis (LCA) or X-linked retinitis pigmentosa (XLRP). In suppression, we suppress the abnormal function of dominant coding segments such as in autosomal dominant retinitis pigmentosa (ADRP).Another consideration is the delivery of the gene (Figure 2)2, and there are two viruses to chose from: adenovirus and lentivirus. A practitioner must consider potential outcomes for both delivery methods and which approach best serves the patient.In a similar process, the practitioner must choose between the currentlyavailable modes of delivery for the injections (Figure 3)1. Subretinal injection is the most common method. The therapeutic is injected into the subretinal space, which necessitates inducing a small retinal detachment. This allows the gene to be delivered directly to the site of the affected cells (retinal pigment epithelial cells and photoreceptors).A table labeled "table 2" displays a pipeline overview of current clinical trials for gene therapies targeting inherited reginal diseasesIntravitreal injection is, in practice, an easier method for gene delivery. The vector is injected into the vitreous and it must reach the target cell population, but most often, affects the inner retinal layers rather than the RPE cells. This method of injection has potential for a greater immune response.There are more than 436 studies of ocular gene therapies. For retinal specialists grappling with diseases once thought “untreatable,” this presents a wide range of viable options. The following is a brief overview of retinal diseases that can benefit from a gene therapy approach, and the current ongoing clinical trials.Retinitis pigmentosaRetinitis pigmentosa (RP)3 affects one in 4000 individuals, with 15% of that population suffering from XLRP. Rod cell damage from RP leads to peripheral vision loss and nyctalopia. The most commonly affected genes include RHO, USH2A and RPGR; 87 other genes have been identified. Inherited RP is associated with conditions such as Bardet-Biedl and Usher syndrome.Gene Trials:MeiraGTx/Janssen:Phase 1/2 trial(NCT03252847) comparing subretinal injection of different doses (low, intermediate and high) with XLRP patients.LUMEOUS phase 3 (NCT04671433) is currently ongoing.AGTC/Beacon Therapeutics:Phase 1/2 SKYLINE (NCT03316560) for XLRPPhase 2/3 study VISTA (NCT04850118) for low/high-dose AGTC0501 with subretinal delivery is currently ongoing.ProQR TherapeuticsAnti-sense oligonucleotidePhase 1/2 trial (NCT04123626) for ADRPPhase 1/2 trial STELLAR (NCT05176717) for Usher syndromeChoroidermiaChoroidermia is an X-linked retinal disease that affects males (one in 50,000); the inherited disease does also have female carriers. Symptoms can include night blindness (poor dark adaptation), retinal pigment epithelium loss, visual field scotoma (ring) and glare. Macula is preserved until later ages. An electroretinogram shows rod and cone degeneration.Gene Trials:4D Molecular TherapeuticsPhase 1/2 trial (NCT04483440) for mutation in CHM gene; R100 vector intravitreal deliveryLeber congenital amaurosisLeber congenital amaurosis is an autosomal recessive disorder. This inherited disease is rare, occurring in two to three out of every 100,000 people. It is characterized by 20/200 or worsevisual acuity, photophobia, nystagmus and sluggish pupils. It is associated with keratoconus, developmental delay, olfactory dysfunction and stereotypical movements.Gene Trials:Spark Therapeutics:Vortigene Neparvovec (Luxturna)First FDA-approved gene therapy for biallelic mutation of RPE65Patients had to navigate obstacle course (multiluminance mobility testing) in phase 3.Treated patients had improved retinal sensitivity and visual fields and were able to pass the multiluminance mobility testing.Visual acuity did not improve and patients who were treated had foveal thinning.Editas Medicine:CRISPR/Cas9Removes point mutation in the CEP290 geneProQR Therapeutics:RNA antisense oligonucleotide to prevent CEP290 abnormal splicingPhase 1/2 clinical trial showing improved visual acuityAtsena Therapeutics:Phase 1/2 dose escalation study GUCY2D-associated LCAOngoingStargardt diseaseStargardt disease is typically an autosomal recessive condition. However, dominant genes connected with this disorder do exist. Fatty tissue builds on the macula, and while the vision loss may begin in childhood, some patients do not suffer vision loss until they are adults. The disease is rare (one in 10,000) and caused by a mutation of the ABCA4 gene, which clears the lipofuscin component A2E from photoreceptors. Visual acuity is frequently preserved but can worsen to 20/400.Gene Trials:SanofiPhase 1/2a study: SAR422459OngoingAlkeusGildeuretinol (ALK-001)AchromatopsiaAchromatopsia affects all 3 cone photoreceptors. Patients may suffer from symptoms including poor visual acuity, photophobia, nystagmus and partial or total color blindness.Gene Trials:MeiraGTx/JanssenPhase 1/2 trials for AAV-CNGB3 in adult and paediatric patientsPhase 1/2 trials for AAV-CNGA3 in paediatric patients (ages 3-15)Applied genetic technologies corporation (AGTC)Phase 1/2 clinical trials for mutations in CNGA3 and CNGB3ReferencesDalkara D, Sahel JA. Gene therapy for inherited retinal degenerations. C R Biol. 2014 Mar;337(3):185-92. doi: 10.1016/j.crvi.2014.01.002. Epub 2014 Mar 11. PMID: 24702845.Carr ME, Tortella BJ. Emerging and future therapies for hemophilia. J Blood Med. 2015 Sep 3;6:245-55. doi: 10.2147/JBM.S42669. PMID: 26366108; PMCID: PMC4562652.Choroidermia fundus collage image. MacDonald IM, Hume S, Zhai Y, et al. Choroideremia. 2003 Feb 21 [Updated 2021 Mar 4]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1337/
本文来源：https://europe.ophthalmologytimes.com/view/inherited-retinal-diseases-and-gene-therapies-a-pharmaceutical-overview
翻译: Monica
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 fill=%23FFFFFF%3E%3Crect x=249 y=126 width=1 height=1%3E%3C/rect%3E%3C/g%3E%3C/g%3E%3C/svg%3E "【国际】遗传性视网膜疾病和基因疗法：药物概述(图10)")
