Spinal muscular atrophy (SMA) is a neuromuscular disorder caused my mutation of the Survival Motor Neuron 1 (SMN1). SMA is characterized by degeneration of motor neurons caused by chronic low levels of SMN. We demonstrated earlier that the c-Jun NH2-terminal kinase (JNK) pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 mediates neurodegeneration in SMA. Genetic inactivation of Jnk3 gene prevents neurodegeneration and improves SMA phenotype. The loss of JNK3 provides neuroprotection, reduces muscle degeneration, improve overall growth and increases lifespan of SMA mice, which shows a systemic rescue of SMA phenotype by an SMN-independent mechanism. Thus, JNK3 represents a potential (non-SMN) therapeutic target for development of an alternative treatment for SMA.
In this study, we examined the effect of known and novel JNK inhibitors on the improvement of SMA phenotype using SMA mouse model. To identify compounds with highest efficacy for protection of SMN-deficient neurons, we examined effect of pan-JNK and JNK3 isoform-selective inhibitor compounds on JNK inhibition and neuroprotection using in vitro cultured primary spinal cord neurons from SMA mice. Selective non-toxic JNK inhibitors, improved in vitro growth of SMN-deficient neurons derived from SMA mice were selected for in vivo testing. Treatments of SMA mice with three compounds with unique chemical scaffolds and ability to cross blood-brain-barrier resulted in decreasing disease severity and improvement of SMA phenotype. Pharmacological inhibition with pan-JNK and selective JNK3 inhibitors did not change levels of SMN but improved overall growth, gross motor function, including ability to right and walk, hind limb strength and increases the lifespan of SMA mice compared to SMA mice treated with vehicle. In conclusion, these findings show pharmacological inhibition of JNK results in amelioration of SMA phenotype in mice and validate JNK as a promising therapeutic target for developing suitable standalone or combinatorial strategies for the treatment of SMA.