Identification of JNK inhibitors that prevent neurodegeneration and improve spinal muscular atrophy


Scientific Other

Poster Number: 189


Laxman Gangwani, PhD



Spinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by degeneration of motor neurons caused by chronic low levels of survival motor neuron (SMN) protein. We showed that the c-Jun NH2-terminal kinase (JNK) pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required form neurodegeneration in SMA. Genetic ablation of Jnk3 slows the progression of disease and improves SMA phenotype. JNK3-deficiency provides neuroprotection, reduces muscle degeneration, improve motor function and overall growth and increases lifespan of SMA mice that shows a systemic rescue of SMA phenotype by an SMN-independent mechanism. Thus, JNK3 represents a potential (non-SMN) therapeutic target for developing the treatment for SMA.

In this study, we examined the effect of JNK inhibitors compounds on the severity of disease and rescue 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. A few compounds that were able to inhibit JNK, prevent neuron degeneration and improved in vitro growth of SMA neurons were selected for in vivo JNK inhibition. Treatments of SMA mice with two JNK inhibitors with unique chemical scaffolds and ability to cross blood-brain-barrier result in improvement of SMA phenotype. Pharmacological JNK inhibition in vivo improves overall growth, gross motor function, including ability to right and walk, hind limb strength and increases the lifespan of SMA mice compared to untreated SMA mice or treated with vehicle. In conclusion, these findings show genetic and 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.