Kannan et al. (Brain Communications, 2026) demonstrate that pharmacological inhibition of c-Jun NH2-terminal kinase (JNK) prevents motor neuron degeneration in SMA models — without affecting SMN levels in spinal cord or skeletal muscle.

Three new JNK inhibitor scaffolds

The work characterizes JNK inhibitors based on three distinct chemical scaffolds: Anthrapyrazolone, Pyrimidinyl, and Pyridopyrimidine. In vivo treatment in SMA mouse models led to systemic improvement in disease phenotype, with enhanced overall growth and improved gross motor function.

Why "SMN-independent" is significant

Most current SMA therapies work by raising SMN protein levels (e.g., risdiplam promotes SMN2 exon 7 inclusion; Zolgensma delivers an SMN1 gene). JNK inhibition acts downstream of SMN — interrupting the motor neuron stress-response pathway that drives degeneration. This makes it conceptually complementary: a JNK inhibitor could be combined with risdiplam or nusinersen for severe SMA, or could serve as a stand-alone option for moderate / mild patients where SMN restoration alone may not address all symptoms.

What's next

Translation to clinical trials would require detailed safety and PK studies of the specific scaffolds — JNK signaling is broadly active in the body, and selectivity for the brain-restricted JNK3 isoform (MAPK10) over peripheral JNK1/JNK2 will be important.

Source: Kannan et al., Brain Communications 2026 (DOI: 10.1093/braincomms/fcag111); SMA Europe May 2026 newsletter.