Keele Research Repository

Spinal muscular atrophy (SMA) is a neuromuscular disease characterised by loss of alpha motor neurons and muscle atrophy. When untreated, mortality occurs within the first two years of life in the most severe cases. Extensive research has led to three approved genebased therapies that significantly prolong the life of SMA patients. Nonetheless, these therapies are unfortunately not a cure and do not fully address the metabolic perturbations present in SMA animal models and patients. The transcription factor Krϋppel-like factor 15 (Klf15) contributes to metabolic homeostasis in metabolically active tissues and is involved in the glucocorticoid-glucocorticoid receptor-Klf15 (GC-GR-Klf15) pathway. We have previously demonstrated aberrant expression of Klf15 in spinal cord and peripheral tissues of SMA mice. We therefore investigated if directly targeting upstream signalling of the GCGR- Klf15 pathway would provide therapeutic benefits.

We firstly validated our previous results and showed that Klf15 expression was increased in skeletal muscle of Smn2B/- mice and in human SMA type III deltoid myoblasts. Next, in cellular models of muscle, neuron, adipose, heart and liver, we demonstrated that mifepristone reduced GC-induced Klf15 expression in a dose- and differentiation state dependent manner. No toxicity or adverse effects on cell proliferation were seen. Importantly, 250 μg/g and 500 μg/g mifepristone significantly improved survival of Smn2B/- SMA mice. Oral gavage of 500 μg/g mifepristone did not improve survival of Smn-/-;SMN2 mice. Mifepristone reduced Klf15 expression in brown adipose tissue (BAT) and increased myofiber area in Smn2B/- mice.

Combinatorial treatment improved weight and survival of Smn2B/- male mice compared to gene therapy alone. Myofiber area was increased and Klf15 expression was reduced in the liver of Smn2B/- mice. Our study provides evidence of aberrant activity of the GC-GR-Klf15 pathway in SMA and highlights the therapeutic potential of the SMN-independent drug mifepristone alone and in combination with a gene therapy.