@article{ab19629f445f44f38b9461b191d45be4,
title = "A NeuroD1 AAV-Based Gene Therapy for Functional Brain Repair after Ischemic Injury through In Vivo Astrocyte-to-Neuron Conversion",
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.",
author = "Chen, {Yu Chen} and Ma, {Ning Xin} and Pei, {Zi Fei} and Zheng Wu and Do-Monte, {Fabricio H.} and Susan Keefe and Emma Yellin and Chen, {Miranda S.} and Yin, {Jiu Chao} and Grace Lee and Ang{\'e}lica Minier-Toribio and Yi Hu and Bai, {Yu Ting} and Kathryn Lee and Quirk, {Gregory J.} and Gong Chen",
note = "Funding Information: This work was supported by grants from the NIH ( AG045656 ) and Alzheimer's Association ( ZEN-15-321972 ) to G.C. It was also supported by the Charles H. Smith Endowment Fund for Brain Repair and the Verne M. Willaman Endowment Fund from the Pennsylvania State University to G.C. The rat fear conditioning test was supported by NIMH grant K99-MH-105549 to F.H.D.-M., NIMH grants R37-MH058883 and P-50-MH-086400 to G.J.Q., and a grant from the University of Puerto Rico President{\textquoteright}s Office to G.J.Q. We would like to thank Matthew Keefe and Joseph Gyekis for careful proof reading of our manuscript. We would also like to thank all the Chen lab members for rigorous discussing throughout this project over the past 5 years. Funding Information: This work was supported by grants from the NIH (AG045656) and Alzheimer's Association (ZEN-15-321972) to G.C. It was also supported by the Charles H. Smith Endowment Fund for Brain Repair and the Verne M. Willaman Endowment Fund from the Pennsylvania State University to G.C. The rat fear conditioning test was supported by NIMH grant K99-MH-105549 to F.H.D.-M. NIMH grants R37-MH058883 and P-50-MH-086400 to G.J.Q. and a grant from the University of Puerto Rico President's Office to G.J.Q. We would like to thank Matthew Keefe and Joseph Gyekis for careful proof reading of our manuscript. We would also like to thank all the Chen lab members for rigorous discussing throughout this project over the past 5 years. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2020",
month = jan,
day = "8",
doi = "10.1016/j.ymthe.2019.09.003",
language = "English (US)",
volume = "28",
pages = "217--234",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "1",
}