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Cells
Volume 14
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10.3390/cells14171318
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Article

Human CAR Tregs Targeting SOD1 and Expressing BDNF Reduce Inflammation and Delay Disease in G93A hSOD1-NSG Mice

by
David J. Graber
1,2,
W. James Cook
1,2,
Marie-Louise Sentman
1,2,
Joana M. Murad-Mabaera
3,
Elijah W. Stommel
4 and
Charles L. Sentman
1,2,*
1
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
2
Center for Synthetic Immunity, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
3
Celdara Medical LLC, 16 Cavendish Court, Lebanon, NH 03766, USA
4
Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
*
Author to whom correspondence should be addressed.
Cells 2025, 14(17), 1318; https://doi.org/10.3390/cells14171318
Submission received: 16 July 2025 / Revised: 19 August 2025 / Accepted: 20 August 2025 / Published: 26 August 2025
(This article belongs to the Section Cell and Gene Therapy)
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Abstract

Regulatory T cells (Tregs) have anti-inflammatory immunomodulatory activity and hold therapeutic potential for chronic neuroinflammatory neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). We are developing engineered human Tregs with enhanced disease-modifying activity for treating ALS. A combination of a disease-specific chimeric antigen receptor (CAR) recognizing misfolded human superoxide dismutase-1 (hSOD1) and constitutive expression of brain-derived neurotrophic factor (BDNF) was tested. The scFv region of CAR demonstrated binding to anterior horn tissues of ALS patients with and without familial ALS mutations in SOD1. Tregs transduced to express BDNF showed the ability to secrete BDNF and protect co-cultured neuronal cells from peroxidase toxicity. Co-expression of BDNF did not inhibit CAR Treg expansion, Treg markers, or CAR-mediated anti-inflammatory cytokine production. Human Tregs co-expressing CAR and BDNF were tested for activity in G93A hSOD1-NSG transgenic mice, which develop an early-onset and aggressive ALS-like disease and do not reject human cells. Human Tregs expressing CAR and BDNF delayed the onset of disease development, extended survival, and decreased spinal cord neuroinflammation. The engineered Tregs showed enhanced disease-modifying activity and hold promise as a therapy for ALS.
Keywords: amyotrophic lateral sclerosis; regulatory T cell; IL-10; inflammation; cell therapy; chimeric antigen receptor amyotrophic lateral sclerosis; regulatory T cell; IL-10; inflammation; cell therapy; chimeric antigen receptor

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MDPI and ACS Style

Graber, D.J.; Cook, W.J.; Sentman, M.-L.; Murad-Mabaera, J.M.; Stommel, E.W.; Sentman, C.L. Human CAR Tregs Targeting SOD1 and Expressing BDNF Reduce Inflammation and Delay Disease in G93A hSOD1-NSG Mice. Cells 2025, 14, 1318. https://doi.org/10.3390/cells14171318

AMA Style

Graber DJ, Cook WJ, Sentman M-L, Murad-Mabaera JM, Stommel EW, Sentman CL. Human CAR Tregs Targeting SOD1 and Expressing BDNF Reduce Inflammation and Delay Disease in G93A hSOD1-NSG Mice. Cells. 2025; 14(17):1318. https://doi.org/10.3390/cells14171318

Chicago/Turabian Style

Graber, David J., W. James Cook, Marie-Louise Sentman, Joana M. Murad-Mabaera, Elijah W. Stommel, and Charles L. Sentman. 2025. "Human CAR Tregs Targeting SOD1 and Expressing BDNF Reduce Inflammation and Delay Disease in G93A hSOD1-NSG Mice" Cells 14, no. 17: 1318. https://doi.org/10.3390/cells14171318

APA Style

Graber, D. J., Cook, W. J., Sentman, M.-L., Murad-Mabaera, J. M., Stommel, E. W., & Sentman, C. L. (2025). Human CAR Tregs Targeting SOD1 and Expressing BDNF Reduce Inflammation and Delay Disease in G93A hSOD1-NSG Mice. Cells, 14(17), 1318. https://doi.org/10.3390/cells14171318

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