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other·preclinical research, biomedical research, ophthalmology, neurology, research methods·PMC10033723

New AAV tools fail to detect Neurod1-mediated neuronal conversion of Müller glia and astrocytes in vivo

eBioMedicine · 5 authors, 4 centres

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TL;DR

The study addresses neuronal leakage in AAV-GFAP-mediated gene delivery of reprogramming factors (Neurod1, Math5, Ascl1, Neurog2) in the adult mouse retina and brain.

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The study addresses neuronal leakage in AAV-GFAP-mediated gene delivery of reprogramming factors (Neurod1, Math5, Ascl1, Neurog2) in the adult mouse retina and brain. These tools significantly reduced neuronal leakage.

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other

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preclinical research

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ORIGINAL PAPER

PMC10033723

New AAV tools fail to detect Neurod1-mediated neuronal conversion of Müller glia and astrocytes in vivo

eBioMedicine

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ABSTRACT

Summary Background Reprogramming resident glial cells to convert them into neurons in vivo represents a potential therapeutic strategy that could replenish lost neurons, repair damaged neural circuits, and restore function. AAV (adeno-associated virus)-based expression systems are powerful tools for in vivo gene delivery in glia-to-neuron reprogramming, however, recent studies show that AAV-based gene delivery of Neurod1 into the mouse brain can cause severe leaky expression into endogenous neurons leading to misinterpretation of glia-to-neuron conversion. Methods AAV-based delivery systems were modified for improved in vivo delivery of Neurod1, Math5, Ascl1, and Neurog2 in the adult mouse retina and brain. To examine whether bona fide glia-to-neuron conversion occurs, stringent fate mapping experiments were performed to trace the lineage of glial cells. Findings The neuronal leakage is prevalent after AAV- GFAP -mediated delivery of Neurod1, Math5, Ascl1, and Neurog2. The transgene-dependent leakage cannot be corrected after lowering the AAV doses, using alterative AAV serotypes or injection routes. Importantly, we report the development of two new AAV-based tools that can significantly reduce neuronal leakage. Using the new AAV-based tools, we provide evidence that Neurod1 gene transfer fails to convert lineage traced glial cells into neurons. Interpretation Stringent fate mapping techniques independently of an AAV-based expression system are the golden standard for tracing the fate of glia cells during neuronal reprogramming. The newly developed AAV-based systems are invaluable tools for glia-to-neuron reprogramming in vivo . Funding The work in Chen lab was supported by National Institutes of Health (NIH) grants R01 EY024986 and R01 EY028921, an unrestricted challenge grant from Research to Prevent Blindness, the New York Eye and Ear Infirmary Foundation, and The Harold W. McGraw, Jr. Family Foundation for Vision Research. The work in Zhang lab was supported by NIH (R01 NS127375 and R01 NS117065) and The Decherd Foundation. Keywords: AAV, Gene delivery, Reprogramming factors, Glial cells, Glia-to-neuron reprogramming

CITATION EXPORT

Ye Xie, Jing Zhou, Lei-Lei Wang et al.. New AAV tools fail to detect Neurod1-mediated neuronal conversion of Müller glia and astrocytes in vivo. eBioMedicine. (2023). https://doi.org/10.1016/j.ebiom.2023.104531

AUTHORS

5 · 4 CENTRES

Ye Xie, Jing Zhou, Lei-Lei Wang, Chun-Li Zhang, Bo Chen

aDepartment of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
bDepartment of Molecular Biology and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
cDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
dDepartment of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA