Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease

Zheng Wu, Matthew Parry, Xiao-Yi Hou, Min-Hui Liu, Hui Wang, Rachel Cain, Zi-Fei Pei, Yu-Chen Chen, Zi-Yuan Guo, Sambangi Abhijeet and Gong Chen ()
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Zheng Wu: Pennsylvania State University
Matthew Parry: Pennsylvania State University
Xiao-Yi Hou: Pennsylvania State University
Min-Hui Liu: Jinan University
Hui Wang: Pennsylvania State University
Rachel Cain: Pennsylvania State University
Zi-Fei Pei: Pennsylvania State University
Yu-Chen Chen: Pennsylvania State University
Zi-Yuan Guo: Pennsylvania State University
Sambangi Abhijeet: Pennsylvania State University
Gong Chen: Pennsylvania State University

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Huntington’s disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32+ medium spiny neurons. The striatal astrocyte-converted neurons showed action potentials and synaptic events, and projected their axons to the targeted globus pallidus and substantia nigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treated R6/2 mice showed a significant extension of life span and improvement of motor functions. This study demonstrates that in vivo AtN conversion may be a disease-modifying gene therapy to treat HD and other neurodegenerative disorders.

Date: 2020
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DOI: 10.1038/s41467-020-14855-3

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