In vivo Neuroregeneration to Treat Ischemic Stroke Through NeuroD1 AAV-Based Gene Therapy in Adult Non-human Primates

Ge, Longjiao; Yang, Fuhan; Li, Wen; Wang, Tao; Lin, Yu Shan; Feng, Jie; Chen, Nanhui; Jiang, Min; Wang, Jianhong; Hu, Xintian; Chen, Gong

doi:10.3389/fcell.2020.590008

Cited by 67 publications

(82 citation statements)

References 75 publications

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“…The results have shown that high expression of a neural transcription factor NeuroD1 in astrocytes can successfully reprogram nearly 90% of infected astrocytes into neurons in the monkey cortex following ischemic stroke, and those neurons could survive over 1 year. The neurons from NeuroD1mediated astrocyte-to-neuron (AtN) conversion displayed Tbr1 + cortical neuron identity and were mostly located in the monkey gray matter (Ge et al, 2020), which is entirely consistent with earlier findings in rodent ischemic stroke models (Chen et al, 2020;Liu et al, 2020). Interestingly, the number and intrinsic proliferative property of astrocytes in the converted areas were not changed compared with those in the control side.…”

Section: Advantages Of Neurod1-mediated Astrocyte-to-neuron Conversion For Evaluating Therapeutic Treatment After Stroke In Adult Non-humsupporting

confidence: 90%

“…Recently, Chen's research group firstly reported that an in situ neuronal regeneration approach using AAV NeuroD1-based gene therapy could repair damaged brains in adult non-human primates (NHPs) with ischemic stroke (Ge et al, 2020). These findings were based on earlier successful investigations in vitro and in vivo (Guo et al, 2014;Brulet et al, 2017;Chen et al, 2020;Wu et al, 2020;Zhang et al, 2020).…”

Section: Advantages Of Neurod1-mediated Astrocyte-to-neuron Conversion For Evaluating Therapeutic Treatment After Stroke In Adult Non-hummentioning

confidence: 99%

“…Moreover, it was extremely attractive that the NeuroD1mediated AtN conversion not only significantly increased the cortical neuronal density, dendritic marker, and synaptic marker levels in the ischemic injured areas of the monkey cortex but also improved the microenvironment, including reducing the number of reactive microglia and macrophages (Ge et al, 2020). The improvement of the inflammatory microenvironment was beneficial for the survival of parvalbumin-positive GABAergic interneurons that were badly damaged by ischemic injury (Povysheva et al, 2019).…”

Section: Advantages Of Neurod1-mediated Astrocyte-to-neuron Conversion For Evaluating Therapeutic Treatment After Stroke In Adult Non-hummentioning

confidence: 99%

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Commentary: In vivo Neuroregeneration to Treat Ischemic Stroke Through NeuroD1 AAV-Based Gene Therapy in Adult Non-human Primates

Zhang

Chen

Wang

2021

Front. Cell Dev. Biol.

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Section: Advantages Of Neurod1-mediated Astrocyte-to-neuron Conversion For Evaluating Therapeutic Treatment After Stroke In Adult Non-humsupporting

confidence: 90%

Section: Advantages Of Neurod1-mediated Astrocyte-to-neuron Conversion For Evaluating Therapeutic Treatment After Stroke In Adult Non-hummentioning

confidence: 99%

Section: Advantages Of Neurod1-mediated Astrocyte-to-neuron Conversion For Evaluating Therapeutic Treatment After Stroke In Adult Non-hummentioning

confidence: 99%

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Commentary: In vivo Neuroregeneration to Treat Ischemic Stroke Through NeuroD1 AAV-Based Gene Therapy in Adult Non-human Primates

Zhang

Chen

Wang

2021

Front. Cell Dev. Biol.

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“…The injection of an adeno-associated virus (AAV) that expressed NeuroD1 was able to convert reactive astrocytes in a severe stab injury model in mice into neurons, while the remaining astrocytes proliferated to repopulate themselves [ 9 ]. Similar findings were found in an in vivo model of adult non-human primates that utilized an ectopic injection of NeuroD1 AAV-based gene therapy in ischemic stroke monkey cortices [ 10 ]. Therefore, gene-based therapeutic approaches that could potentially reverse or provide neuroprotection against RGC death would address many optic neuropathies.…”

Section: Introductionsupporting

confidence: 80%

Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

Rhee

Shih

2021

Biomolecules

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We systematically reviewed published translational research on gene-based therapy for retinal ganglion cell (RGC) neuroprotection. A search was conducted on Entrez PubMed on 23 December 2020 using the keywords “gene therapy”, “retinal ganglion cell” and “neuroprotection. The initial search yielded 82 relevant articles. After restricting publications to those with full text available and in the English language, and then curating for only original articles on gene-based therapy, the final yield was 18 relevant articles. From the 18 papers, 17 of the papers utilized an adeno-associated viral (AAV) vector for gene therapy encoding specific genes of interest. Specifically, six of the studies utilized an AAV vector encoding brain-derived neurotrophic factor (BDNF), two of the studies utilized an AAV vector encoding erythropoietin (EPO), the remaining 10 papers utilized AAV vectors encoding different genes and one microRNA study. Although the literature shows promising results in both in vivo and in vitro models, there is still a significant way to go before gene-based therapy for RGC neuroprotection can proceed to clinical trials. Namely, the models of injury in many of the studies were more acute in nature, unlike the more progressive and neurodegenerative pathophysiology of diseases, such as glaucoma. The regulation of gene expression is also highly unexplored despite the use of AAV vectors in the majority of the studies reviewed. It is also expected that with the successful launch of messenger ribonucleic acid (mRNA)-based vaccinations in 2020, we will see a shift towards this technology for gene-based therapy in glaucoma neuroprotection.

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“…We recently reported that ectopic expression of a single neural transcription factor, NeuroD1, efficiently converted astrocytes into neurons 9,[25][26][27][28][29][30][31] . NeuroD1, together with Neurog2 and Ascl1, belongs to the basic helix-loop-helix (bHLH) family of neural transcription factors, and plays critical roles in the induction of neural differentiation during early brain development 11,[32][33][34][35][36] .…”

Section: Efficient Neuronal Conversion Of Human Gbm Cellsmentioning

confidence: 99%

Transcription factor-based gene therapy to treat glioblastoma through direct neuronal conversion

Wang¹,

Pei²,

Hossain³

et al. 2021

Cancer Biol. Med.

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Objective: Glioblastoma (GBM) is the most prevalent and aggressive adult primary cancer in the central nervous system. Therapeutic approaches for GBM treatment are under intense investigation, including the use of emerging immunotherapies. Here, we propose an alternative approach to treat GBM through reprogramming proliferative GBM cells into non-proliferative neurons. Methods: Retroviruses were used to target highly proliferative human GBM cells through overexpression of neural transcription factors. Immunostaining, electrophysiological recording, and bulk RNA-seq were performed to investigate the mechanisms underlying the neuronal conversion of human GBM cells. An in vivo intracranial xenograft mouse model was used to examine the neuronal conversion of human GBM cells. Results: We report efficient neuronal conversion from human GBM cells by overexpressing single neural transcription factor Neurogenic differentiation 1 (NeuroD1), Neurogenin-2 (Neurog2), or Achaete-scute homolog 1 (Ascl1). Subtype characterization showed that the majority of Neurog2-and NeuroD1-converted neurons were glutamatergic, while Ascl1 favored GABAergic neuron generation. The GBM cell-converted neurons not only showed pan-neuronal markers but also exhibited neuron-specific electrophysiological activities. Transcriptome analyses revealed that neuronal genes were activated in glioma cells after overexpression of neural transcription factors, and different signaling pathways were activated by different neural transcription factors. Importantly, the neuronal conversion of GBM cells was accompanied by significant inhibition of GBM cell proliferation in both in vitro and in vivo models. Conclusions: These results suggest that GBM cells can be reprogrammed into different subtypes of neurons, leading to a potential alternative approach to treat brain tumors using in vivo cell conversion technology.

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In vivo Neuroregeneration to Treat Ischemic Stroke Through NeuroD1 AAV-Based Gene Therapy in Adult Non-human Primates

Cited by 67 publications

References 75 publications

Commentary: In vivo Neuroregeneration to Treat Ischemic Stroke Through NeuroD1 AAV-Based Gene Therapy in Adult Non-human Primates

Commentary: In vivo Neuroregeneration to Treat Ischemic Stroke Through NeuroD1 AAV-Based Gene Therapy in Adult Non-human Primates

Use of Gene Therapy in Retinal Ganglion Cell Neuroprotection: Current Concepts and Future Directions

Transcription factor-based gene therapy to treat glioblastoma through direct neuronal conversion

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