Targeting low levels of MIF expression as a potential therapeutic strategy for ALS

Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by motor neurons (MNs) loss. We previously discovered that macrophage migration inhibitory factor (MIF), whose levels are extremely low in spinal MNs, inhibits mutant SOD1 misfolding and toxicity. In this study, we show that a single peripheral injection of adeno-associated virus (AAV) delivering MIF into adult SOD1G37R mice, significantly improved their motor function, delayed disease progression and extended survival. Moreover, MIF treatment reduced neuroinflammation and misfolded SOD1 accumulation, rescued MNs and corrected dysregulated pathways as observed by proteomics and transcriptomics. Furthermore, we revealed low MIF levels in human induced pluripotent stem cell derived MNs from familial ALS patients with different genetic mutations, as well as in post-mortem tissues of sporadic ALS patients. Our findings indicate that peripheral MIF administration may provide a potential therapeutic mechanism for modulating misfolded SOD1 in vivo and disease outcome in ALS patients. Overall design: RNA from the lumbar spinal cord of non-transgenic and SOD1-G37R transgenic mice not treated or treated with AAV-PHP.eB-MIF using single tail-vein injection after the disease onset.