Repair of Retinal Degeneration following Ex Vivo Minicircle DNA Gene Therapy and Transplantation of Corrected Photoreceptor Progenitors
Repair of Retinal Degeneration following Ex Vivo Minicircle DNA Gene Therapy and Transplantation of Corrected Photoreceptor Progenitors
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DOI：
10.1016/j.ymthe.2020.01.023
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发表时间：
2020-03-04
影响因子：
12.4
通讯作者：
MacLaren, Robert E.
中科院分区：
文献类型：
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作者：
Barnea-Cramer, Alona O.;Singh, Mandeep;MacLaren, Robert E.
作者描述了利用一种新的体外基因治疗和细胞移植方法，在缺失视紫红质基因的遗传性失明小鼠中进行视网膜重建和视觉功能恢复。具有相同染色体基因突变的光感受器前体在体外使用微环DNA处理，微环DNA是一种非病毒技术，不存在腺相关病毒（AAV）载体的包装限制。移植后，基因修饰的细胞重建了具有相同创始基因突变的失明小鼠的功能视网膜并支持视力。在传递缺失基因方面，微环的基因传递表现出与AAV相当的长期效率，这是首个对光感受器进行强效治疗的非病毒系统。这一重要的概念验证发现为遗传性神经退行性疾病的治疗提供了一种创新的细胞和基因疗法的融合，并可能在未来的研究中应用于患者特异性细胞的体外校正，以提供一种自体组织来源来替代遗传性视网膜失明中失去的光感受器。这是第一个在光感受器祖细胞中使用微环的报道，也是第一个移植矫正后的光感受器前体来恢复失明动物视力的报道。
The authors describe retinal reconstruction and restoration of visual function in heritably blind mice missing the rhodopsin gene using a novel method of ex vivo gene therapy and cell transplantation. Photoreceptor precursors with the same chromosomal genetic mutation were treated ex vivo using minicircle DNA, a non-viral technique that does not present the packaging limitations of adeno-associated virus (AAV) vectors. Following transplantation, genetically modified cells reconstructed a functional retina and supported vision in blind mice harboring the same founder gene mutation. Gene delivery by minicircles showed comparable long-term efficiency to AAV in delivering the missing gene, representing the first non-viral system for robust treatment of photoreceptors. This important proof-of-concept finding provides an innovative convergence of cell and gene therapies for the treatment of hereditary neuro-degenerative disease and may be applied in future studies toward ex vivo correction of patient-specific cells to provide an autologous source of tissue to replace lost photoreceptors in inherited retinal blindness. This is the first report using minicircles in photoreceptor progenitors and the first to transplant corrected photoreceptor precursors to restore vision in blind animals.