Modeling complex age-related eye disease

IF 18.6 1区 医学 Q1 OPHTHALMOLOGY Progress in Retinal and Eye Research Pub Date : 2024-02-15 DOI:10.1016/j.preteyeres.2024.101247
Silke Becker , Zia L'Ecuyer , Bryan W. Jones , Moussa A. Zouache , Fiona S. McDonnell , Frans Vinberg
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Abstract

Modeling complex eye diseases like age-related macular degeneration (AMD) and glaucoma poses significant challenges, since these conditions depend highly on age-related changes that occur over several decades, with many contributing factors remaining unknown. Although both diseases exhibit a relatively high heritability of >50%, a large proportion of individuals carrying AMD- or glaucoma-associated genetic risk variants will never develop these diseases. Furthermore, several environmental and lifestyle factors contribute to and modulate the pathogenesis and progression of AMD and glaucoma.

Several strategies replicate the impact of genetic risk variants, pathobiological pathways and environmental and lifestyle factors in AMD and glaucoma in mice and other species. In this review we will primarily discuss the most commonly available mouse models, which have and will likely continue to improve our understanding of the pathobiology of age-related eye diseases. Uncertainties persist whether small animal models can truly recapitulate disease progression and vision loss in patients, raising doubts regarding their usefulness when testing novel gene or drug therapies. We will elaborate on concerns that relate to shorter lifespan, body size and allometries, lack of macula and a true lamina cribrosa, as well as absence and sequence disparities of certain genes and differences in their chromosomal location in mice.

Since biological, rather than chronological, age likely predisposes an organism for both glaucoma and AMD, more rapidly aging organisms like small rodents may open up possibilities that will make research of these diseases more timely and financially feasible. On the other hand, due to the above-mentioned anatomical and physiological features, as well as pharmacokinetic and -dynamic differences small animal models are not ideal to study the natural progression of vision loss or the efficacy and safety of novel therapies. In this context, we will also discuss the advantages and pitfalls of alternative models that include larger species, such as non-human primates and rabbits, patient-derived retinal organoids, and human organ donor eyes.

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复杂的老年性眼病模型
建立年龄相关性黄斑变性(AMD)和青光眼等复杂眼病的模型是一项重大挑战,因为这些疾病在很大程度上取决于数十年的年龄相关性变化,而许多诱发因素仍然未知。虽然这两种疾病的遗传率相对较高,超过 50%,但很大一部分携带 AMD 或青光眼相关遗传风险变异的个体永远不会患上这些疾病。此外,一些环境和生活方式因素也会导致和调节老年性黄斑变性和青光眼的发病和发展。有几种策略在小鼠和其他物种中复制了遗传风险变异、病理生物学途径以及环境和生活方式因素对老年性黄斑变性和青光眼的影响。在这篇综述中,我们将主要讨论最常见的小鼠模型,这些模型已经并将继续增进我们对老年性眼病病理生物学的了解。小动物模型能否真正再现患者的疾病进展和视力丧失仍存在不确定性,这使我们对其在测试新型基因或药物疗法时的实用性产生了怀疑。我们将详细阐述与小鼠较短的寿命、体型和异体、缺乏黄斑和真正的颅底膜以及某些基因的缺失和序列差异及其染色体位置差异有关的问题。由于生物年龄(而非时间年龄)可能使生物体更容易患青光眼和老年性视网膜病变,因此,小型啮齿类动物等衰老更快的生物体可能会使这些疾病的研究更及时、更经济可行。另一方面,由于上述解剖和生理特点以及药代动力学和动力学差异,小型动物模型并不是研究视力丧失的自然进展或新型疗法的有效性和安全性的理想选择。在这种情况下,我们还将讨论包括非人类灵长类动物和兔子、患者视网膜器官组织以及人体器官捐献者眼睛等大型物种在内的替代模型的优势和缺陷。
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来源期刊
CiteScore
34.10
自引率
5.10%
发文量
78
期刊介绍: Progress in Retinal and Eye Research is a Reviews-only journal. By invitation, leading experts write on basic and clinical aspects of the eye in a style appealing to molecular biologists, neuroscientists and physiologists, as well as to vision researchers and ophthalmologists. The journal covers all aspects of eye research, including topics pertaining to the retina and pigment epithelial layer, cornea, tears, lacrimal glands, aqueous humour, iris, ciliary body, trabeculum, lens, vitreous humour and diseases such as dry-eye, inflammation, keratoconus, corneal dystrophy, glaucoma and cataract.
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