Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas.
Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas.
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DOI：
10.1084/jem.20220776
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发表时间：
2023-05-01
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影响因子：
--
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秦和他的同事开发了一种基因组编辑工具，其特点是主要编辑的多功能性和SPRY的不受限制的PAM要求。体内基因纠正成功地在Pde6b相关的视网膜色素变性小鼠模型中实施，导致了大量的视力功能挽救。视网膜色素变性是一种遗传性视网膜营养不良，导致视网膜光感受器的进行性和不可逆性丧失。在这里，我们开发了一个基因组编辑工具，其特征是主要编辑程序(PE)的多功能性和SpCas9变体(SPRY)的不受限制的PAM要求，称为PESpRY。Pde6b相关RP小鼠模型的病变视网膜通过包装PESpRY的双重AAV系统进行转导，以便通过非NGG PAM(GTG)进行体内基因组编辑。一旦突变被纠正，进行中的细胞损失就会被逆转，导致光感受器的大量挽救和功能性PDE6β的产生。经处理的小鼠在视网膜电信号上表现出显著的反应，在被动和主动回避测试中都表现出良好的表现。此外，他们在视觉刺激驱动的视觉运动反应方面有明显的改善，并有效地完成了视觉引导的水迷宫任务。总之，我们的研究提供了令人信服的证据，证明通过在退化的视网膜中进行不受限制的主要编辑，可以预防由RP相关基因突变引起的视力丧失。
Qin and colleagues develop a genome-editing tool characterized by the versatility of prime editors and unconstrained PAM requirement of SpRY. In vivo gene correction is successfully implemented in the mouse model of Pde6b-associated retinitis pigmentosa, leading to substantial functional rescue of vision. Retinitis pigmentosa (RP) is an inherited retinal dystrophy causing progressive and irreversible loss of retinal photoreceptors. Here, we developed a genome-editing tool characterized by the versatility of prime editors (PEs) and unconstrained PAM requirement of a SpCas9 variant (SpRY), referred to as PESpRY. The diseased retinas of Pde6b-associated RP mouse model were transduced via a dual AAV system packaging PESpRY for the in vivo genome editing through a non-NGG PAM (GTG). The progressing cell loss was reversed once the mutation was corrected, leading to substantial rescue of photoreceptors and production of functional PDE6β. The treated mice exhibited significant responses in electroretinogram and displayed good performance in both passive and active avoidance tests. Moreover, they presented an apparent improvement in visual stimuli-driven optomotor responses and efficiently completed visually guided water-maze tasks. Together, our study provides convincing evidence for the prevention of vision loss caused by RP-associated gene mutations via unconstrained in vivo prime editing in the degenerating retinas.
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影响因子：
64.8
作者：
Komor AC;Kim YB;Packer MS;Zuris JA;Liu DR
通讯作者：
Liu DR
影响因子：
28.1
作者：
Kim, Hui Kwon;Lee, Sungtae;Kim, Hyongbum Henry
通讯作者：
Kim, Hyongbum Henry
DOI：
10.1056/nejmoa1412965
发表时间：
2015-05-14
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jacobson SG;Cideciyan AV;Roman AJ;Sumaroka A;Schwartz SB;Heon E;Hauswirth WW
通讯作者：
Hauswirth WW
影响因子：
64.8
作者：
Anzalone, Andrew V.;Randolph, Peyton B.;Liu, David R.
通讯作者：
Liu, David R.
影响因子：
16.6
作者：
Choi EH;Suh S;Foik AT;Leinonen H;Newby GA;Gao XD;Banskota S;Hoang T;Du SW;Dong Z;Raguram A;Kohli S;Blackshaw S;Lyon DC;Liu DR;Palczewski K
通讯作者：
Palczewski K