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In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

Long-Jiao Ge, Fu-Han Yang, Jie Feng, Nan-Hui Chen, Min Jiang, Jian-Hong Wang, Xin-Tian Hu, Gong Chen
doi: https://doi.org/10.1101/816066
Long-Jiao Ge
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
7Kunming College of Life Science, University of the Chinese Academy of Sciences, Kunming, Yunnan 650204, China
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  • For correspondence: gongchenpsu@yahoo.com
Fu-Han Yang
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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Jie Feng
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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Nan-Hui Chen
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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Min Jiang
4State Key Laboratory of Medical Neurobiology and MOE Frontier Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
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Jian-Hong Wang
6Kunming Primates Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan650223, China
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  • For correspondence: gongchenpsu@yahoo.com
Xin-Tian Hu
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
5CAS Center for Excellence in Brain Science, Chinese Academy of Sciences, Shanghai, 200031, China
6Kunming Primates Research Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan650223, China
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  • For correspondence: gongchenpsu@yahoo.com
Gong Chen
1Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
2Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China
3Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
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  • For correspondence: gongchenpsu@yahoo.com
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ABSTRACT

Stroke is a leading cause of death and disability but most of the clinical trials have failed in the past, despite our increasing understanding of the molecular and pathological mechanisms underlying stroke. While many signaling pathways have been identified in the aftermath of stroke, the majority of current approaches are focusing on neural protection rather than neuroregeneration. In this study, we report an in vivo neural regeneration approach to convert brain internal reactive astrocytes into neurons through ectopic expression of a neural transcription factor NeuroD1 in adult non-human primate (NHP) brains following ischemic stroke. We demonstrate that NeuroD1 AAV-based gene therapy can convert reactive astrocytes into neurons with high efficiency (90%), but astrocytes are never depleted in the NeuroD1-expressed areas, consistent with the proliferative capability of astrocytes. The NeuroD1-mediated in vivo astrocyte-to-neuron (AtN) conversion in monkey cortex following ischemic stroke increased local neuronal density, reduced reactive microglia, and surprisingly protected parvalbumin interneurons in the converted areas. The NeuroD1 gene therapy showed a broad time window, from 10 days to 30 days following ischemic stroke, in terms of exerting its neuroregenerative and neuroprotective effects. The cortical astrocyte-converted neurons also showed Tbr1+ cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, suggesting a potential self-regulatory mechanism of NeuroD1 in adult mature neurons of NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons in adult primate brains for tissue repair.

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Posted November 01, 2019.
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In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy
Long-Jiao Ge, Fu-Han Yang, Jie Feng, Nan-Hui Chen, Min Jiang, Jian-Hong Wang, Xin-Tian Hu, Gong Chen
bioRxiv 816066; doi: https://doi.org/10.1101/816066
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In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy
Long-Jiao Ge, Fu-Han Yang, Jie Feng, Nan-Hui Chen, Min Jiang, Jian-Hong Wang, Xin-Tian Hu, Gong Chen
bioRxiv 816066; doi: https://doi.org/10.1101/816066

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