Eye-APC Duke-NUS Medical School, Singapore, 169856, Singapore; Institute of Ophthalmology, University College London, London, W2 1PG, UK; Imperial College of Science and Technology, St. Mary's Campus, London, WC1E 6BT, UK; Department of Pharmacy Sciences, Creighton University, Omaha, NE, 68178, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, 77004, USA; Department of Pharmacology and Neuroscience, University of North Texas Health Sciences Center, Fort Worth, TX, 76107, USA; Singapore Eye Research Institute, Singapore, 169856, Singapore; Global Research & Development, Nanoscope Therapeutics Inc., Dallas, TX 75207, USA.
Mol Aspects Med. 2023 Dec;94:101218. doi: 10.1016/j.mam.2023.101218. Epub 2023 Nov 15.
More than 76 million people worldwide are afflicted with the neurodegenerative eye diseases described and grouped together as glaucoma. A common feature amongst the many forms of glaucoma is chronically elevated intraocular pressure (IOP) within the anterior chamber of the eye that physically damages the retina, optic nerve and parts of the brain connected with visual perception. The mediators of the contusing raised IOP responsible for such damage and loss of vision include locally released inflammatory agents, tissue remodeling enzymes and infiltrating immune cells which damage the retinal ganglion cell (RGC) axons and eventually kill a significant number of the RGCs. Additional culprits include genetic defects of the patient that involve aberrations in receptors, enzymes and/or endogenous ligands and possible over- or under-production of the latter. Other genetic abnormalities may include issues with signal transduction machinery within key cells of critical tissues in the front (e.g. trabecular meshwork [TM] and Schlemm's canal [SC]) and back of the eye (e.g. retinal ganglion cells and their axons). Genome-wide associated studies (GWAS) coupled with next generation sequencing have provided powerful linkage of certain gene defects and polymorphic variants to the onset and progression of diseases of the tissues involved in fluid dynamics in the TM and SC, and many retinal elements (lamina cribosa, optic nerve head) at the back of the eye which cause ocular hypertension (OHT) and glaucomatous optic neuropathy (GON), respectively. Despite the availability of some drugs, fluid drainage microshunts and full surgical techniques to lower and control intraocular pressure, the major modifiable biomarker of open-angle and other forms of glaucoma, their side-effect profiles, less than optimum effectiveness and short duration of action present opportunities to clinically manage the glaucomas with next generation of treatments with high therapeutic indices, including gene therapies. Thus, identification, characterization and deployment of genetic data coupled with traditional drug discovery and novel gene replacement, gene editing and genetic engineering technologies may provide some solutions to the aforementioned problems. These aspects will be discussed in this article.
全世界有超过 7600 万人患有描述和归类为青光眼的神经退行性眼病。许多形式的青光眼的一个共同特征是眼内前房内慢性升高的眼内压 (IOP)，这种压力会对视网膜、视神经和与视觉感知相关的大脑部分造成物理损伤。导致IOP 升高并导致这种损伤和视力丧失的介质包括局部释放的炎症介质、组织重塑酶和浸润免疫细胞，这些介质会损伤视网膜神经节细胞 (RGC) 轴突，最终导致大量 RGC 死亡。其他罪魁祸首包括涉及受体、酶和/或内源性配体异常以及后者过度或不足产生的患者的遗传缺陷。其他遗传异常可能包括关键组织中关键细胞的信号转导机制问题，这些组织包括前部（例如小梁网 [TM] 和施莱姆氏管 [SC]）和后部的眼（例如视网膜神经节细胞及其轴突）。全基因组关联研究 (GWAS) 与下一代测序相结合，为特定基因缺陷和多态性变体与 TM 和 SC 中流体动力学以及许多后部视网膜元素（筛板、视神经头）相关疾病的发病和进展之间提供了强大的联系，这些疾病分别导致眼内高压 (OHT) 和青光眼视神经病变 (GON)。尽管有一些药物、液体引流微分流和完整的手术技术可以降低和控制眼内压，但开角型和其他形式青光眼的主要可改变生物标志物、其副作用特征、效果不理想和作用持续时间短，为使用具有高治疗指数的下一代治疗方法来临床管理青光眼提供了机会，包括基因治疗。因此，结合传统药物发现和新型基因替代、基因编辑和基因工程技术，识别、表征和部署遗传数据可能为解决上述问题提供一些解决方案。本文将讨论这些方面。
