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.
Highlights
Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease
To evaluate cell-based gene transduction efficiency in BM-derived cells (BMDCs) after infection with a lentiviral vector (LV) and BM transplantation (BMT), we first constructed a yellow fluorescence protein (YFP) expression vector driven by elongation factor (EF)-1 (BOS) promotor (Fig. 1a, LV-BOS-YFP)
Our current study combined gene therapy with stem cells, which showed that BMDCs expressing GLT1 by the LV in transgenic SOD1(G93A) mice resulted in expression of GLT1 at segments of the spinal cord and led to an extension of lifespan and improved motor functions
Summary
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). 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. The current treatment is based on symptom management and respiratory support with only a few approved medications, which provide modest benefits in some patients[1,2] Treatment of this fatal neurodegenerative disease remains obscure because its pathophysiology is not well understood. Wild type BM cells and hematopoietic stem cells transplanted into SOD1(G93A) mice, an ALS model, have been shown to preserve motor functions and prolong the survival of the mice[18]. A large number of Scientific Reports | (2021) 11:12803
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
