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在 AIPL1 相关莱伯先天性黑矇的视网膜类器官模型中研究 PTC124 介导的翻译通读。

Investigation of PTC124-mediated translational readthrough in a retinal organoid model of AIPL1-associated Leber congenital amaurosis.

机构信息

UCL Institute of Ophthalmology, London EC1V 9EL, UK.

UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK.

出版信息

Stem Cell Reports. 2022 Oct 11;17(10):2187-2202. doi: 10.1016/j.stemcr.2022.08.005. Epub 2022 Sep 8.

DOI:10.1016/j.stemcr.2022.08.005
PMID:36084639
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9561542/
Abstract

Leber congenital amaurosis type 4 (LCA4), caused by AIPL1 mutations, is characterized by severe sight impairment in infancy and rapidly progressing degeneration of photoreceptor cells. We generated retinal organoids using induced pluripotent stem cells (iPSCs) from renal epithelial cells obtained from four children with AIPL1 nonsense mutations. iPSC-derived photoreceptors exhibited the molecular hallmarks of LCA4, including undetectable AIPL1 and rod cyclic guanosine monophosphate (cGMP) phosphodiesterase (PDE6) compared with control or CRISPR-corrected organoids. Increased levels of cGMP were detected. The translational readthrough-inducing drug (TRID) PTC124 was investigated as a potential therapeutic agent. LCA4 retinal organoids exhibited low levels of rescue of full-length AIPL1. However, this was insufficient to fully restore PDE6 in photoreceptors and reduce cGMP. LCA4 retinal organoids are a valuable platform for in vitro investigation of novel therapeutic agents.

摘要

Leber 先天性黑蒙 4 型（LCA4）是由 AIPL1 突变引起的，其特征是婴儿期严重视力障碍和光感受器细胞快速进行性退化。我们使用从四个患有 AIPL1 无义突变的儿童的肾上皮细胞中获得的诱导多能干细胞（iPSC）生成了视网膜类器官。与对照或 CRISPR 校正的类器官相比，iPSC 衍生的光感受器表现出 LCA4 的分子特征，包括无法检测到的 AIPL1 和杆状环鸟苷酸单磷酸（cGMP）磷酸二酯酶（PDE6）。检测到 cGMP 水平升高。研究了翻译通读诱导药物（TRID）PTC124 作为潜在的治疗药物。LCA4 视网膜类器官显示全长 AIPL1 的挽救水平较低。然而，这不足以完全恢复光感受器中的 PDE6 并降低 cGMP。LCA4 视网膜类器官是体外研究新型治疗药物的有价值平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/4c0af225e58b/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/bb95305418f9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/7d627630abc5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/0f020ca6926b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/13c687e51b37/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/8bbadb508733/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/65bafc9e7298/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/4c0af225e58b/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/bb95305418f9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/7d627630abc5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/0f020ca6926b/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/13c687e51b37/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/8bbadb508733/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/65bafc9e7298/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fb6/9561542/4c0af225e58b/gr7.jpg

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本文引用的文献

1
Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms.氨苯砜和氨基糖苷类通过正交机制刺激无义密码子通读。
Proc Natl Acad Sci U S A. 2021 Jan 12;118(2). doi: 10.1073/pnas.2020599118.
2
Retinal organoids: a window into human retinal development.视网膜类器官：探索人类视网膜发育的窗口。
Development. 2020 Dec 24;147(24):dev189746. doi: 10.1242/dev.189746.
3
Translational Read-Through Therapy of Nonsense Mutations.翻译：无义突变的翻译通读疗法。
Stem Cell Rev Rep. 2025 Jan;21(1):167-197. doi: 10.1007/s12015-024-10802-7. Epub 2024 Oct 18.
4
Limb Girdle Muscular Dystrophy Type 2B (LGMD2B): Diagnosis and Therapeutic Possibilities.肢带型肌营养不良 2B 型（LGMD2B）：诊断与治疗的可能。
Int J Mol Sci. 2024 May 21;25(11):5572. doi: 10.3390/ijms25115572.
5
Effective AAV-mediated gene replacement therapy in retinal organoids modeling AIPL1-associated LCA4.在模拟与AIPL1相关的LCA4的视网膜类器官中进行有效的腺相关病毒介导的基因替代疗法。
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6
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Acta Naturae. 2023 Oct-Dec;15(4):56-64. doi: 10.32607/actanaturae.25454.
7
Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases.诱导多能干细胞和类器官在遗传性视网膜疾病中的应用。
Stem Cell Res Ther. 2023 Nov 27;14(1):340. doi: 10.1186/s13287-023-03564-5.
8
variants causing retinitis pigmentosa or Usher syndrome provoke differential retinal phenotypes in disease-specific organoids.导致视网膜色素变性或乌谢尔综合征的变异在疾病特异性类器官中引起不同的视网膜表型。
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9
Human Retinal Organoids in Therapeutic Discovery: A Review of Applications.人类视网膜类器官在治疗性发现中的应用综述。
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10
Pharmaceuticals Promoting Premature Termination Codon Readthrough: Progress in Development.促进过早终止密码子通读的药物：开发进展。
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Int J Mol Sci. 2020 Nov 10;21(22):8418. doi: 10.3390/ijms21228418.
4
Clinical and functional analyses of AIPL1 variants reveal mechanisms of pathogenicity linked to different forms of retinal degeneration.临床和功能分析表明 AIPL1 变异与不同形式的视网膜变性相关的致病机制。
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5
Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy.对无义突变型杜氏肌营养不良症中阿托伦随机对照试验的荟萃分析。
J Comp Eff Res. 2020 Oct;9(14):973-984. doi: 10.2217/cer-2020-0095. Epub 2020 Aug 27.
6
Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids.利用 iPSC 衍生的视网膜类器官对 RP2 型视网膜炎进行建模和挽救。
Stem Cell Reports. 2020 Jul 14;15(1):67-79. doi: 10.1016/j.stemcr.2020.05.007. Epub 2020 Jun 11.
7
Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1.源自 AIPL1-LCA 患者 hiPSC 的视网膜类器官在降低突变 AIPL1 水平的情况下仍保持细胞结构。
Sci Rep. 2020 Mar 25;10(1):5426. doi: 10.1038/s41598-020-62047-2.
8
Nonsense suppression induced readthrough of a novel PAX6 mutation in patient-derived cells of congenital aniridia.无义抑制诱导先天性无虹膜患者来源细胞中新型 PAX6 突变的通读。
Mol Genet Genomic Med. 2020 May;8(5):e1198. doi: 10.1002/mgg3.1198. Epub 2020 Mar 3.
9
Rhapsody: predicting the pathogenicity of human missense variants.Rhapsody：预测人类错义变异的致病性。
Bioinformatics. 2020 May 1;36(10):3084-3092. doi: 10.1093/bioinformatics/btaa127.
10
Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations.依伐布雷定治疗致病变异引起的长 QT 间期综合征 2A 型
Int J Mol Sci. 2019 Dec 12;20(24):6274. doi: 10.3390/ijms20246274.