Haloperidol induces neuroprotection and enhances neuromuscular function in both murine and human models of spinal muscular atrophy

Abstract Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by Survival Motor Neuron 1 ( SMN1 ) gene mutations, leading to reduced SMN protein levels and progressive motor neuron (MN) degeneration. Although current therapies aim to restore SMN expression, limitations highlight the need for alternative strategies. We investigated haloperidol (HALO), a classical antipsychotic, as a potential therapeutic based on its ability to enhance SMN2 splicing and SMN expression. Using the delta 7 SMA mouse model, we assessed effects of HALO on survival, motor function, neuroprotection, and neuroinflammation, by histological, molecular, and RNA-sequencing analyses of spinal cord and muscle samples. Additionally, we examined patient induced pluripotent stem cell-derived MNs and myotube co-cultures for validation in human cells. HALO increased lifespan and motor performance in mice with SMA, upregulated SMN protein in spinal cord and muscles, reduced MN loss, and attenuated neuroinflammation. Moreover, HALO enhanced neuromuscular junction integrity and muscle trophism, suggesting peripheral benefits. RNA-sequencing analysis revealed extensive splicing changes, including SMN target transcripts, supporting enhanced activity. In human models, HALO improved MN survival and SMN expression, supporting dual SMN-dependent and neuroprotective mechanisms. Given its central nervous system penetrance and clinical approval, HALO emerges as a promising SMA therapy candidate, warranting further dose optimization and validation for translational potential.