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bioRxiv · 10.1101/2023.08.10.552842

IL-1Ra and CCL5, but not IL-10, are promising targets for treating SMA astrocyte-driven pathology

Allison, R. L.·Suneja, M.·LaCroix, M.·Harmelink, M.·Ebert, A.
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Abstract

Spinal muscular atrophy (SMA) is a pediatric genetic disorder characterized by the loss of spinal cord motor neurons. Although the mechanisms underlying motor neuron loss are not clear, current data suggest that glial cells contribute to disease pathology. We have previously found that SMA astrocytes drive microglial activation and motor neuron loss potentially through the upregulation of NFkB-mediated pro-inflammatory cytokines. In this study, we tested the ability of increasing either interleukin 10 (IL-10) or IL-1 receptor antagonist (IL-1ra) while neutralizing C-C motif chemokine ligand 5 (CCL5) to reduce the pro-inflammatory phenotype of SMA astrocytes. While IL-10 was ineffective, IL-1ra ameliorated SMA astrocyte-driven glial activation and motor neuron loss in iPSC-derived cultures in vitro. In vivo AAV5 delivered IL-1ra overexpression and miR-30 shRNA knockdown of CCL5 had modest but significant improvements on lifespan, weight gain, and motor function of SMN{Delta}7 mice. Together these data identify IL-1ra and CCL5 as possible therapeutic targets for SMA and highlight the importance of glial-targeted therapeutics for neurodegenerative disease.

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Allison, R. L., Suneja, M., LaCroix, M., Harmelink, M., Ebert, A.. 2023-08-14. IL-1Ra and CCL5, but not IL-10, are promising targets for treating SMA astrocyte-driven pathology. https://doi.org/10.1101/2023.08.10.552842

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