What was reported

Vrettou, Müller, Zetzsche and Wirth (University of Cologne) presented multi-organ proteomics in the Taiwanese SMA mouse model + ASO-treated controls at the 5th International Scientific Congress on SMA (Budapest 2026, oral O16).

Mechanism

NRF2 (gene NFE2L2) is the master transcription factor for the antioxidant response. Its negative regulator is KEAP1. Pharmacological activation of the NRF2-KEAP1 axis — by KEAP1 inhibitors or covalent modifiers — upregulates HMOX1, NQO1, glutathione-synthesis enzymes (GCLC, GCLM) and other downstream cytoprotective genes.

Findings

• Multi-organ proteomics across 7 tissues × 5 experimental groups (WT, het, SMA, ± SMN-augmenting ASO)
• Mitochondrial-redox perturbations PERSIST despite ASO treatment in neuronal and muscular organs — the redox layer of SMA pathology is not fully addressed by SMN restoration alone
• In liver: partial recovery of NRF2-KEAP1 axis after ASO; heme biosynthesis remained unrecovered
• Kidney: unique disruption of ER–mitochondria redox crosstalk, fully rescued by ASO — first kidney proteomics dataset in this model
• In SMA Type 1 patient–derived fibroblasts: pharmacological NRF2 activation significantly increased proliferation vs control

Why this matters

If NRF2 axis dysfunction is downstream of SMN deficiency but not corrected by ASO, then NRF2 activators are a complementary therapy class. Several activators are already FDA-approved for adjacent neurological / metabolic indications: omaveloxolone (Skyclarys, Friedreich Ataxia 2023), dimethyl fumarate (Tecfidera, MS). Sulforaphane and bardoxolone methyl are in preclinical / Phase 3 development.

This is an early signal, presented as a Congress oral. The fibroblast rescue does not yet establish clinical benefit. Replication in motor neuron models and rodent in vivo is needed.