视网膜下递送aav5介导的人Pde6b基因改善了视网膜色素变性大鼠模型的疾病表型。

IF 1.8 3区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Vision Pub Date : 2025-03-29 eCollection Date: 2025-01-01

Hee Jong Kim, Ji Hoon Kwak, Jun Sub Choi, Jin Kim, Seo Yun Moon, Steven Hyun Seung Lee, Heuiran Lee, Keerang Park, Joo Yong Lee, So-Yoon Won

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引用次数: 0

摘要

目的：一种影响人类环鸟苷单磷酸酯-磷酸二酯酶6型(PDE6B) β亚基的遗传疾病导致常染色体隐性视网膜色素变性（RP）。由于光感受器的快速退化，这种情况会在生命早期导致严重的视力丧失。在Pde6b基因敲除（KO）引起的RP大鼠模型中，本研究评估了腺相关病毒（AAV）5介导的人Pde6b基因在视网膜下递送的治疗潜力。方法：比较不同血清型（2、5、8）AAV在Pde6b KO大鼠体内的转导效率和趋向性，发现AAV5在光感受器中的表达最高，特异性最强。我们在出生后21天将AAV5-Pde6b注射到Pde6b KO大鼠的视网膜下间隙。我们通过测量PDE6B蛋白表达、光感受器结构、视网膜形态和厚度、视网膜色素上皮完整性和视觉功能来评估注射后6周的保护作用。结果：AAV5-Pde6b治疗通过恢复Pde6b蛋白表达，保持光感受器结构，改善视网膜形态和厚度，维持视网膜色素上皮完整性，改善Pde6b KO大鼠的疾病表型。通过暗位视网膜电图（ERG）和眼球震颤的视觉功能分析显示，与注射aav5 - gfp的Pde6b基因KO大鼠相比，AAV5-Pde6b治疗可显著改善Pde6b基因KO大鼠的视觉功能。结论：我们的研究结果表明AAV5-Pde6b可能是Pde6b突变引起的RP的潜在治疗基因候选。

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Subretinal delivery of AAV5-mediated human Pde6b gene ameliorates the disease phenotype in a rat model of retinitis pigmentosa.

Purpose: A genetic disorder that affects the beta subunit of cyclic guanosine monophosphate-phosphodiesterase type 6 (PDE6B) in humans leads to autosomal recessive retinitis pigmentosa (RP). This condition causes severe vision loss in early life due to fast deterioration of photoreceptors. This study evaluated the therapeutic potential of subretinal delivery of the adeno-associated virus (AAV)5-mediated human Pde6b gene in an RP rat model caused by Pde6b gene knockout (KO).

Methods: We compared the transduction efficiency and tropism of different AAV serotypes (2, 5 and 8) in Pde6b KO rats and found that AAV5 had the highest and most specific expression in photoreceptors. We injected AAV5-Pde6b into the subretinal space of Pde6b KO rats on postnatal day 21. We assessed the protective effects six weeks postinjection by measuring PDE6B protein expression, photoreceptor structure, retinal morphology and thickness, retinal pigment epithelium integrity and visual function.

Results: AAV5-Pde6b treatment ameliorated the disease phenotype in Pde6b KO rats by restoring PDE6B protein expression, preserving photoreceptor structure, improving retinal morphology and thickness, and maintaining retinal pigment epithelium integrity. Functional analysis of vision by scotopic electroretinogram (ERG) and optokinetic nystagmus revealed that AAV5-Pde6b treatment significantly improved the visual function of Pde6b gene KO rats compared with AAV5-GFP-injected Pde6b KO rats.

Conclusions: Our results demonstrate that AAV5-Pde6b may be a potential therapeutic gene candidate for RP caused by Pde6b mutations.

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来源期刊

Molecular Vision 生物-生化与分子生物学

CiteScore

4.40

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： Molecular Vision is a peer-reviewed journal dedicated to the dissemination of research results in molecular biology, cell biology, and the genetics of the visual system (ocular and cortical). Molecular Vision publishes articles presenting original research that has not previously been published and comprehensive articles reviewing the current status of a particular field or topic. Submissions to Molecular Vision are subjected to rigorous peer review. Molecular Vision does NOT publish preprints. For authors, Molecular Vision provides a rapid means of communicating important results. Access to Molecular Vision is free and unrestricted, allowing the widest possible audience for your article. Digital publishing allows you to use color images freely (and without fees). Additionally, you may publish animations, sounds, or other supplementary information that clarifies or supports your article. Each of the authors of an article may also list an electronic mail address (which will be updated upon request) to give interested readers easy access to authors.