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

Abstract

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.

• Authors: Natsuko Ohashi, Tomoya Terashima, Miwako Katagi, Yuki Nakae, Junko Okano, Yoshihisa Suzuki, Hideto Kojima
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 12803 (06 17 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 34140581 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Cytokines
• Excitatory Amino Acid Transporter 2
• RNA, Messenger
• Slc1a2 protein, mouse
• Glutamic Acid
• Superoxide Dismutase-1

Topics

• Amyotrophic Lateral Sclerosis (complications, physiopathology)
• Animals
• Biomarkers (metabolism)
• Bone Marrow Cells (metabolism)
• Bone Marrow Transplantation
• Cell Survival
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Disease Progression
• Excitatory Amino Acid Transporter 2 (genetics)
• Gene Expression Regulation
• Gene Transfer Techniques
• Genetic Therapy
• Gliosis (complications, pathology, physiopathology)
• Glutamic Acid (metabolism)
• Lentivirus (metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (metabolism)
• Motor Activity (physiology)
• Motor Neurons (metabolism)
• Muscular Atrophy (complications, pathology, physiopathology)
• Nerve Degeneration (complications, pathology, physiopathology)
• RNA, Messenger (genetics, metabolism)
• Spinal Cord (metabolism)
• Superoxide Dismutase-1 (metabolism)
• Survival Analysis
• Mice