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开发一种可翻译的基因增强疗法，用于治疗 CNGB1 型色素性视网膜炎。

Development of a translatable gene augmentation therapy for CNGB1-retinitis pigmentosa.

机构信息

College of Veterinary Medicine, Michigan State University, 736 Wilson Road, East Lansing, MI 48864, USA.

Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; Department of Ophthalmology, University Hospital, LMU Munich, 80336 Munich, Germany.

出版信息

Mol Ther. 2023 Jul 5;31(7):2028-2041. doi: 10.1016/j.ymthe.2023.04.005. Epub 2023 Apr 13.

DOI:10.1016/j.ymthe.2023.04.005
PMID:37056049
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10362398/
Abstract

In this study, we investigate a gene augmentation therapy candidate for the treatment of retinitis pigmentosa (RP) due to cyclic nucleotide-gated channel beta 1 (CNGB1) mutations. We use an adeno-associated virus serotype 5 with transgene under control of a novel short human rhodopsin promoter. The promoter/capsid combination drives efficient expression of a reporter gene (AAV5-RHO-eGFP) exclusively in rod photoreceptors in primate, dog, and mouse following subretinal delivery. The therapeutic vector (AAV5-RHO-CNGB1) delivered to the subretinal space of CNGB1 mutant dogs restores rod-mediated retinal function (electroretinographic responses and vision) for at least 12 months post treatment. Immunohistochemistry shows human CNGB1 is expressed in rod photoreceptors in the treated regions as well as restoration of expression and trafficking of the endogenous alpha subunit of the rod CNG channel required for normal channel formation. The treatment reverses abnormal accumulation of the second messenger, cyclic guanosine monophosphate, which occurs in rod photoreceptors of CNGB1 mutant dogs, confirming formation of a functional CNG channel. In vivo imaging shows long-term preservation of retinal structure. In conclusion, this study establishes the long-term efficacy of subretinal delivery of AAV5-RHO-CNGB1 to rescue the disease phenotype in a canine model of CNGB1-RP, confirming its suitability for future clinical development.

摘要

在这项研究中，我们研究了一种针对因环核苷酸门控通道 β 1（CNGB1）突变引起的色素性视网膜炎（RP）的基因增强治疗候选物。我们使用了一种腺相关病毒血清型 5，其转基因受新型短人视紫红质启动子的控制。该启动子/衣壳组合在灵长类动物、犬和小鼠的视网膜下递送后，可有效地在杆状光感受器中表达报告基因（AAV5-RHO-eGFP）。将治疗性载体（AAV5-RHO-CNGB1）递送至 CNGB1 突变犬的视网膜下空间，可恢复杆状介导的视网膜功能（视网膜电图反应和视力）至少 12 个月。免疫组织化学显示，在治疗区域的杆状光感受器中表达了人 CNGB1，并且恢复了正常通道形成所需的内源性杆状 CNG 通道的α亚基的表达和运输。该治疗方法逆转了在 CNGB1 突变犬的杆状光感受器中发生的第二信使环鸟苷单磷酸的异常积累，证实了功能性 CNG 通道的形成。体内成像显示视网膜结构的长期保存。总之，这项研究确立了视网膜下递送至 AAV5-RHO-CNGB1 以挽救 CNGB1-RP 犬模型中的疾病表型的长期疗效，证实了其适合未来的临床开发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/6da96fba74e2/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/692545977052/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/f12bb5a518e9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/cfb91f99de1e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/0997af20442e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/81b6404426e6/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/c5e7685e37b5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/fef52132ed64/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/6da96fba74e2/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/692545977052/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/f12bb5a518e9/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/cfb91f99de1e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/0997af20442e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/81b6404426e6/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/c5e7685e37b5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/fef52132ed64/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e33f/10362398/6da96fba74e2/gr7.jpg

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