Drug Discovery Strategies for Inherited Retinal Degenerations.
Drug Discovery Strategies for Inherited Retinal Degenerations.
复制标题
DOI：
10.3390/biology11091338
复制
发表时间：
2022-09-10
期刊：
影响因子：
4.2
通讯作者：
Imanishi, Yoshikazu
中科院分区：
文献类型：
--
作者：
Das, Arupratan;Imanishi, Yoshikazu
关键词：
遗传性视网膜变性是一组异质性的遗传性视力损害疾病。在这些疾病中，感光细胞或视网膜神经节细胞功能失调并退化。目前，还没有治愈这些毁灭性致盲疾病的方法。在这篇综述中，我们将讨论遗传性视网膜变性的靶点和药物发现策略，包括动物模型、干细胞和小分子筛选，以及临床前发展的最新进展。遗传性视网膜变性是一种致盲疾病，全世界每4000人中就有1人患有此病。这些疾病经常引起感光细胞或视网膜神经节细胞的死亡。在这些疾病的一个子集中，感光细胞死亡是视网膜色素上皮细胞功能障碍或变性的继发性后果。本文回顾了目前在确定目标和开发基于小分子的治疗这些破坏性的神经元变性方面的努力，目前尚无治愈方法。光感受器和视网膜神经节细胞由于其独特的结构和功能特性而需要代谢。代谢途径的调节，在大多数遗传性视网膜变性中被破坏，作为有希望的治疗策略。在单基因疾病中，先前获得了与缺陷途径相关的靶标的重大见解，包括光转导，视觉周期和有丝分裂。除了这些基于靶标的药物发现之外，我们还将讨论如何利用表型筛选来发现有益分子，而无需事先了解其作用机制。由于主要的解剖学和生物学差异，用小动物如啮齿动物来模拟人类遗传性视网膜变性状况经常是具有挑战性的。干细胞技术的最新进展为获得人类视网膜神经节细胞和视网膜类器官和光感受器细胞的纯群体开辟了新的途径。我们将讨论利用基于干细胞的疾病模型进行药物发现和临床前开发的并行想法。
Inherited retinal degeneration is a group of heterogeneous genetic disorders impairing vision. In these diseases, photoreceptor or retinal ganglion cells become dysfunctional and degenerate. Currently, no cures exist for these devastating blinding conditions. In this review, we will discuss targets and drug discovery strategies for inherited retinal degeneration using animal models, stem cells, and small molecule screening with updates on preclinical developments. Inherited retinal degeneration is a group of blinding disorders afflicting more than 1 in 4000 worldwide. These disorders frequently cause the death of photoreceptor cells or retinal ganglion cells. In a subset of these disorders, photoreceptor cell death is a secondary consequence of retinal pigment epithelial cell dysfunction or degeneration. This manuscript reviews current efforts in identifying targets and developing small molecule-based therapies for these devastating neuronal degenerations, for which no cures exist. Photoreceptors and retinal ganglion cells are metabolically demanding owing to their unique structures and functional properties. Modulations of metabolic pathways, which are disrupted in most inherited retinal degenerations, serve as promising therapeutic strategies. In monogenic disorders, great insights were previously obtained regarding targets associated with the defective pathways, including phototransduction, visual cycle, and mitophagy. In addition to these target-based drug discoveries, we will discuss how phenotypic screening can be harnessed to discover beneficial molecules without prior knowledge of their mechanisms of action. Because of major anatomical and biological differences, it has frequently been challenging to model human inherited retinal degeneration conditions using small animals such as rodents. Recent advances in stem cell-based techniques are opening new avenues to obtain pure populations of human retinal ganglion cells and retinal organoids with photoreceptor cells. We will discuss concurrent ideas of utilizing stem-cell-based disease models for drug discovery and preclinical development.
登录
查看更多内容
DOI：
10.1126/science.aad8266
发表时间：
2016-08-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen Y;Clarke OB;Kim J;Stowe S;Kim YK;Assur Z;Cavalier M;Godoy-Ruiz R;von Alpen DC;Manzini C;Blaner WS;Frank J;Quadro L;Weber DJ;Shapiro L;Hendrickson WA;Mancia F
通讯作者：
Mancia F
影响因子：
4.8
作者：
Chen, Yu;Okano, Kiichiro;Palczewski, Krzysztof
通讯作者：
Palczewski, Krzysztof
DOI：
10.1523/jneurosci.5956-09.2010
发表时间：
2010-04-21
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Baltan S;Inman DM;Danilov CA;Morrison RS;Calkins DJ;Horner PJ
通讯作者：
Horner PJ
影响因子：
3.5
作者：
Chi ZL;Akahori M;Obazawa M;Minami M;Noda T;Nakaya N;Tomarev S;Kawase K;Yamamoto T;Noda S;Sasaoka M;Shimazaki A;Takada Y;Iwata T
通讯作者：
Iwata T
DOI：
10.1073/pnas.072557799
发表时间：
2002-04-16
影响因子：
11.1
作者：
Alfinito, PD;Townes-Anderson, E
通讯作者：
Townes-Anderson, E