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犬类贝斯特病作为一种转化模型。

Canine Best disease as a translational model.

作者信息

Aguirre Gustavo D, Beltran William A

机构信息

Division of Experimental Retinal Therapies, Department of Clinical Sciences, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, 19104, USA.

出版信息

Eye (Lond). 2025 Feb;39(3):412-417. doi: 10.1038/s41433-024-03578-0. Epub 2025 Jan 7.

Abstract

In this review, we summarize the findings of several pre-clinical studies in the canine BEST1 disease model. To this end, client-owned and purpose bred dogs that were compound heterozygotes or homozygotes, respectively, for two or one of 3 different mutations in BEST1 were evaluated by ophthalmic examination, cSLO/sdOCT imaging, and retinal immunohistochemistry to characterize the clinical and microanatomic features of the disease. Subsequently AAV-mediated gene therapy was done to transfer the BEST1 transgene to the RPE under control of a hVMD2 promoter. We demonstrated that canine bestrophinopathies are an RPE-photoreceptor interface disease with underdeveloped RPE apical microvilli that invest rod and cone outer segments. This leads to microdetachments which later progress to clinically evident RPE-retinal separation and a spectrum of disease stages, ranging from vitelliform to vitelliruptive/atrophic lesions, similar to Best Vitelliform Macular Dystrophy (BVMD). Gene therapy corrects the microdetachments and reverses large lesions when delivered at the pseudohypopyon stage of disease. Because of the similar clinical and microstructural abnormalities between the canine model and BVMD, and positive response to gene therapy, the canine model is a valuable translational model for developing gene and other therapies for BVMD.

摘要

在本综述中,我们总结了在犬类BEST1疾病模型中进行的多项临床前研究的结果。为此,分别对因BEST1基因3种不同突变中的两种或一种而成为复合杂合子或纯合子的客户拥有犬和定向培育犬进行了眼科检查、共聚焦扫描激光眼底镜/扫频光学相干断层扫描(cSLO/sdOCT)成像以及视网膜免疫组化,以表征该疾病的临床和微观解剖特征。随后进行了腺相关病毒(AAV)介导的基因治疗,以在人VMD2启动子的控制下将BEST1转基因转移至视网膜色素上皮(RPE)。我们证明犬类贝斯特罗蛋白病是一种RPE-光感受器界面疾病,其RPE顶端微绒毛发育不全,无法包裹视杆和视锥细胞的外节。这会导致微脱离,随后发展为临床上明显的RPE-视网膜分离以及一系列疾病阶段,从卵黄样病变到卵黄样破裂/萎缩性病变,类似于Best卵黄样黄斑营养不良(BVMD)。在疾病的假前房积脓阶段进行基因治疗时,可纠正微脱离并逆转大的病变。由于犬类模型与BVMD之间存在相似的临床和微观结构异常,且对基因治疗有阳性反应,因此该犬类模型是开发针对BVMD的基因治疗和其他治疗方法的有价值的转化模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01e1/11794707/2e98ff9f258b/41433_2024_3578_Fig1_HTML.jpg

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