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GLT1 gene delivery based on bone marrow-derived cells ameliorates motor function and survival in a mouse model of ALS.

OHASHI Natsuko 60816776 TERASHIMA Tomoya 40378485 KATAGI Miwako 40732459 NAKAE Yuki 40638186 OKANO Junko 50447968 SUZUKI Yoshihisa 30243025 KOJIMA Hideto 00225434 0000-0002-4781-2052 滋賀医科大学

2021.06.17

概要

Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease. CD68-positive bone marrow (BM)-derived cells (BMDCs) accumulate in the pathological lesion in the SOD1(G93A) ALS mouse model after BM transplantation (BMT). Therefore, we investigated whether BMDCs can be applied as gene carriers for cell-based gene therapy by employing the accumulation of BMDCs. In ALS mice, YFP reporter signals were observed in 12-14% of white blood cells (WBCs) and in the spinal cord via transplantation of BM after lentiviral vector (LV) infection. After confirmation of gene transduction by LV with the CD68 promoter in 4-7% of WBCs and in the spinal cord of ALS mice, BM cells were infected with LVs expressing glutamate transporter (GLT) 1 that protects neurons from glutamate toxicity, driven by the CD68 promoter, which were transplanted into ALS mice. The treated mice showed improvement of motor behaviors and prolonged survival. Additionally, interleukin (IL)-1β was significantly suppressed, and IL-4, arginase 1, and FIZZ were significantly increased in the mice. These results suggested that GLT1 expression by BMDCs improved the spinal cord environment. Therefore, our gene therapy strategy may be applied to treat neurodegenerative diseases such as ALS in which BMDCs accumulate in the pathological lesion by BMT.

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Acknowledgements

We thank the investigators at the Central Research Laboratory Shiga University of Medical Science for their

technical support. This study was supported by MEXT KAKENHI Grant JP18K07498 and research funding

from the Takeda Science Foundation. The drawings of vector components were created with PowerPoint 2019

(Microsoft, Redmond, WA) by N.O. and T.T.

Author contributions

N.O. conducted the experiments, analyzed the data, and wrote the manuscript. T.T. provided advice on the

experimental procedures, designed the study, and assisted with writing and revising the manuscript. H.K., Y.S.,

J.O., Y.N., and M.K. provided advice on the experimental design and techniques, expertise, and feedback. All

authors reviewed the final manuscript.

Competing interests The authors declare no competing interests.

Additional information

Supplementary Information The online version contains supplementary material available at https://​doi.​org/​

10.​1038/​s41598-​021-​92285-x.

Correspondence and requests for materials should be addressed to T.T.

Reprints and permissions information is available at www.nature.com/reprints.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and

institutional affiliations.

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