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

摘要

Huntington’s disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the lossof striatal GABAergic neurons and motor functional deficits. We report here an in vivo cellconversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 andDlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion ratereached 80% in the striatum and 50% of the converted neurons were DARPP32+ mediumspiny neurons. The striatal astrocyte-converted neurons showed action potentials andsynaptic events, and projected their axons to the targeted globus pallidus and substantianigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treatedR6/2 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 genetherapy to treat HD and other neurodegenerative disorders.