Combination of stem cell and gene therapy ameliorates symptoms in Huntington's disease mice.

• Type of Material: Article
• Authors: In Ki Cho, Emory University; Carissa Emerson Hunter, Yerkes National Primate Research Center; Sarah Ye, Yerkes National Primate Research Center; Alvince Learnz Pongos, Yerkes National Primate Research Center; Anthony Chan, Emory University
• Language: English
• Date: 2019
• Publisher: Future Medicine
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Springer Nature Publishing AG
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41536-019-0066-7
• Title of Journal or Parent Work: Regenerative Medicine
• ISSN: 1746-0751
• Volume: 4
• Start Page: 7
• End Page: 7
• Grant/Funding Information: YNPRC is supported by the Office of Research and Infrastructure Program (ORIP)/OD P51OD11132.; This study is supported by a grant awarded by the ORIP/NIH (OD010930) and NINDS/NIH (NS084163) to A.W.S.C.
• Research Categories: Biology, Neuroscience; Biology, Genetics

Abstract

Huntington's disease (HD) is a dominantly inherited monogenetic disorder characterized by motor and cognitive dysfunction due to neurodegeneration. The disease is caused by the polyglutamine (polyQ) expansion at the 5' terminal of the exon 1 of the huntingtin (HTT) gene, IT15, which results in the accumulation of mutant HTT (mHTT) aggregates in neurons and cell death. The monogenetic cause and the loss of specific neural cell population make HD a suitable candidate for stem cell and gene therapy. In this study, we demonstrate the efficacy of the combination of stem cell and gene therapy in a transgenic HD mouse model (N171-82Q; HD mice) using rhesus monkey (Macaca mulatta) neural progenitor cells (NPCs). We have established monkey NPC cell lines from induced pluripotent stem cells (iPSCs) that can differentiate into GABAergic neurons in vitro as well as in mouse brains without tumor formation. Wild-type monkey NPCs (WT-NPCs), NPCs derived from a transgenic HD monkey (HD-NPCs), and genetically modified HD-NPCs with reduced mHTT levels by stable expression of small-hairpin RNA (HD-shHD-NPCs), were grafted into the striatum of WT and HD mice. Mice that received HD-shHD-NPC grafts showed a significant increase in lifespan compared to the sham injection group and HD mice. Both WT-NPC and HD-shHD-NPC grafts in HD mice showed significant improvement in motor functions assessed by rotarod and grip strength. Also, immunohistochemistry demonstrated the integration and differentiation. Our results suggest the combination of stem cell and gene therapy as a viable therapeutic option for HD treatment.