A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion.,Molecular Therapy

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A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion.
Molecular Therapy ( IF 12.1 ) Pub Date : 2019-09-06 , DOI: 10.1016/j.ymthe.2019.09.003
Yu-Chen Chen ₁ , Ning-Xin Ma ₁ , Zi-Fei Pei ₁ , Zheng Wu ₁ , Fabricio H Do-Monte ₂ , Susan Keefe ₁ , Emma Yellin ₁ , Miranda S Chen ₁ , Jiu-Chao Yin ₁ , Grace Lee ₁ , Angélica Minier-Toribio ₂ , Yi Hu ₁ , Yu-Ting Bai ₁ , Kathryn Lee ₁ , Gregory J Quirk ₂ , Gong Chen ₃

Affiliation

Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury.

中文翻译：

一种基于 NeuroD1 AAV 的基因疗法，用于通过体内星形胶质细胞到神经元的转化进行缺血性损伤后的功能性脑修复。

成年哺乳动物的大脑在很大程度上失去了神经再生能力，除了少数壁龛。以前的研究已经将神经胶质细胞转化为神经元，但产生的神经元总数有限，治疗潜力尚不清楚。在这里，我们证明了 NeuroD1 介导的原位星形胶质细胞向神经元的转化可以在缺血性损伤后再生大量功能性新神经元。具体来说，使用基于 NeuroD1 腺相关病毒 (AAV) 的基因治疗，我们能够再生缺血性损伤引起的全部丢失神经元的三分之一，同时保护另外三分之一的受伤神经元，从而显着恢复神经元。RNA 测序和免疫染色证实了细胞转化后 mRNA 水平和蛋白质水平的神经元恢复。脑切片记录发现，在 NeuroD1 表达后 2 个月，星形胶质细胞转化的神经元表现出强烈的动作电位和突触反应。顺行和逆行追踪显示从星形胶质细胞转换的神经元到其目标区域的长程轴突投射以时间依赖性方式。行为分析显示细胞转化后运动和认知功能都有显着改善。总之，这些结果表明，通过基于 NeuroD1 的基因治疗的体内细胞转化技术可以再生大量功能性新神经元，以恢复受伤后失去的神经元功能。顺行和逆行追踪显示从星形胶质细胞转换的神经元到其目标区域的长程轴突投射以时间依赖性方式。行为分析显示细胞转化后运动和认知功能都有显着改善。总之，这些结果表明，通过基于 NeuroD1 的基因治疗的体内细胞转化技术可以再生大量功能性新神经元，以恢复受伤后失去的神经元功能。顺行和逆行追踪显示从星形胶质细胞转换的神经元到其目标区域的长程轴突投射以时间依赖性方式。行为分析显示细胞转化后运动和认知功能都有显着改善。总之，这些结果表明，通过基于 NeuroD1 的基因治疗的体内细胞转化技术可以再生大量功能性新神经元，以恢复受伤后失去的神经元功能。

更新日期：2019-09-07

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