Repair of Retinal Degeneration following Ex Vivo Minicircle DNA Gene Therapy and Transplantation of Corrected Photoreceptor Progenitors.,Molecular Therapy

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Repair of Retinal Degeneration following Ex Vivo Minicircle DNA Gene Therapy and Transplantation of Corrected Photoreceptor Progenitors.
Molecular Therapy ( IF 12.1 ) Pub Date : 2020-01-29 , DOI: 10.1016/j.ymthe.2020.01.023
Alona O Barnea-Cramer ₁ , Mandeep Singh ₂ , Dominik Fischer ₃ , Samantha De Silva ₄ , Michelle E McClements ₁ , Alun R Barnard ₁ , Robert E MacLaren ₄

Affiliation

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 neurodegenerative 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.

中文翻译：

体外微圆DNA基因治疗后视网膜变性的修复和正确的光感受器祖细胞的移植。

作者介绍了一种使用离体基因治疗和细胞移植的新方法，在缺少视紫红质基因的遗传性盲小鼠中进行视网膜重建和视觉功能的恢复。使用微环DNA体外处理具有相同染色体遗传突变的感光受体前体，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，转基因细胞重建了具有相同创始人基因突变的盲小鼠的功能性视网膜并支持了视力。通过微圆传递基因在传递缺失的基因方面显示出与AAV相当的长期效率，代表了第一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细胞和基因疗法的创新融合，并可在未来的研究中用于离体校正患者特异性细胞，以提供自体组织来替代丢失的组织遗传性视网膜失明中的感光细胞。这是第一个在感光细胞祖细胞中使用小圆圈的报告，也是第一个移植校正的感光细胞前体以恢复盲动物视力的报告。

更新日期：2020-01-29

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