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三重载体可提高视网膜内 AAV 的转导容量。

Triple Vectors Expand AAV Transfer Capacity in the Retina.

机构信息

Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy.

Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli 80078, Italy; Armenise/Harvard Laboratory of Integrative Genomics, TIGEM, Pozzuoli 80078, Italy.

出版信息

Mol Ther. 2018 Feb 7;26(2):524-541. doi: 10.1016/j.ymthe.2017.11.019. Epub 2017 Dec 5.

DOI:10.1016/j.ymthe.2017.11.019
PMID:29292161
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5835116/
Abstract

Retinal gene transfer with adeno-associated viral (AAV) vectors holds great promise for the treatment of inherited retinal degenerations (IRDs). One limit of AAV is its transfer capacity of about 5 kb, which can be expanded to about 9 kb, using dual AAV vectors. This strategy would still not suffice for treatment of IRDs such as Usher syndrome type 1D or Alström syndrome type I (ALMS) due to mutations in CDH23 or ALMS1, respectively. To overcome this limitation, we generated triple AAV vectors, with a maximal transfer capacity of about 14 kb. Transcriptomic analysis following triple AAV transduction showed the expected full-length products along a number of aberrant transcripts. However, only the full-length transcripts are efficiently translated in vivo. We additionally showed that approximately 4% of mouse photoreceptors are transduced by triple AAV vectors and showed correct localization of recombinant ALMS1. The low-photoreceptor transduction levels might justify the modest and transient improvement we observe in the retina of a mouse model of ALMS. However, the levels of transduction mediated by triple AAV vectors in pig retina reached 40% of those observed with single vectors, and this bodes well for further improving the efficiency of triple AAV vectors in the retina.

摘要

腺相关病毒 (AAV) 载体的视网膜基因转移为遗传性视网膜变性 (IRDs) 的治疗带来了很大的希望。AAV 的一个限制是其转移能力约为 5kb，可以使用双 AAV 载体将其扩展到约 9kb。由于 CDH23 或 ALMS1 中的突变，这种策略对于治疗例如 1 型乌谢尔综合征或 1 型阿尔斯特伦姆综合征 (ALMS) 等 IRD 仍然不够。为了克服这一限制，我们生成了最大转移能力约为 14kb 的三 AAV 载体。三重 AAV 转导后的转录组分析显示了预期的全长产物以及许多异常转录本。然而，只有全长转录本在体内被有效地翻译。我们还表明，大约 4%的小鼠感光细胞被三 AAV 载体转导，并显示出重组 ALMS1 的正确定位。低感光细胞转导水平可能解释了我们在 ALMS 小鼠模型的视网膜中观察到的适度和短暂的改善。然而，三重 AAV 载体在猪视网膜中的转导水平达到了单载体的 40%，这为进一步提高三重 AAV 载体在视网膜中的效率提供了良好的前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/f48ab8b3f009/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/c8b03cf24296/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/99cbce699f7a/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/712fe144792e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/d92915ff0026/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/d0228c2cd92c/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/5a2ab01a5cbc/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/36f282c87212/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/0996295210c6/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/f48ab8b3f009/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/c8b03cf24296/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/99cbce699f7a/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/712fe144792e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/d92915ff0026/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/d0228c2cd92c/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/5a2ab01a5cbc/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/36f282c87212/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/0996295210c6/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ad9/5835116/f48ab8b3f009/gr8.jpg

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