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PreprintCited by 101Neurogenesis and neuroplasticity mechanismsVirus-based gene therapy researchNeuroinflammation and Neurodegeneration Mechanisms

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

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Ge, Long-Jiao, Yang, Fu-Han, Feng, Jie, Chen, Nan-Hui, Jiang, Min, Wang, Jian-Hong, Hu, Xin-Tian, Chen, Gong·2019·Frontiers in Cell and Developmental Biology
DOI 10.1101/816066PMC PMC7674285

Preprint — published as 10.3389/fcell.2020.590008

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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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Metadata

Authors
Ge, L.-J., Yang, F.-H., Feng, J., Chen, N.-H., Jiang, M., Wang, J.-H., Hu, X.-T., & Chen, G.
Affiliations
  • Kunming Institute of Zoology (CN)
  • Fudan University (CN)
  • Pennsylvania State University (US)
Corresponding author
Chen, Gong
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
openRxiv
Published
2019-11-01
Volume
8
Pages
590008-590008
ISSN
2296-634X (ISSN-L)
DOI
10.1101/816066
PMC
PMC7674285
OpenAlex
W3097361880
Cited by
101
References
1
Citations by year
2026: 9 · 2025: 10 · 2024: 20 · 2023: 20 · 2022: 18 · 2021: 18 · 2020: 5
FWCI
6.00
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Innovative Research Group Project of the National Natural Science Foundation of China
  • National Natural Science Foundation of China (2019B030335001, 31571109, U1801681, 2018B030332001, 2019FA007)
  • Chinese Academy of Sciences (XDB32060200)
  • Institute of Zoology, Chinese Academy of Sciences
  • Kunming Institute of Zoology, Chinese Academy of Sciences
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
ischemic stroke, nerve regeneration, NeuroD1, AAV gene therapy, astrocyte-to-neuron conversion, reactive astrocytes, parvalbumin interneurons, cortical stroke, non-human primates, Tbr1, neuronal identity, microglia, adult neurogenesis

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