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Mol Ther. 2019 Sep 6. pii: S1525-0016(19)30404-6. doi: 10.1016/j.ymthe.2019.09.003. [Epub ahead of print]

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

Author information

1
Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
2
Departments of Psychiatry and Anatomy & Neurobiology, University of Puerto Rico School of Medicine, P.O. Box 365067, San Juan 00936-5067, Puerto Rico.
3
Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA; Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China. Electronic address: gongchen@psu.edu.

Abstract

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.

KEYWORDS:

AAV; NeuroD1; astrocyte-to-neuron conversion; brain repair; fear conditioning learning; gene therapy; ischemic injury; motor function

PMID:
31551137
DOI:
10.1016/j.ymthe.2019.09.003
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