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

Spinal muscular atrophy (SMA) is a pediatric genetic disorder characterized by the loss of spinal cord motor neurons (MNs). Although the mechanisms underlying MN 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 MN loss potentially through the upregulation of NF-κB-mediated pro-inflammatory cytokines. In this study, we tested the ability of neutralizing C-C motif chemokine ligand 5 (CCL5) while increasing either interleukin-10 (IL-10) or IL-1 receptor antagonist (IL-1ra) to reduce the pro-inflammatory phenotype of SMA astrocytes. While IL-10 was ineffective, IL-1ra ameliorated SMA astrocyte-driven glial activation and MN loss in induced pluripotent stem cell-derived cultures in vitro. In vivo AAV5 delivered IL-1ra overexpression, and miR-30 small hairpin RNA knockdown of CCL5 made modest but significant improvements in lifespan, weight gain, MN number, and motor function of SMNΔ7 mice. These data identify IL-1ra and CCL5 as possible therapeutic targets for SMA and highlight the importance of glial-targeted therapeutics for neurodegenerative disease.