The brain penetrant PPARγ agonist leriglitazone restores multiple altered pathways in models of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD), a potentially fatal neurometabolic disorder with no effective pharmacological treatment, is characterized by clinical manifestations ranging from progressive spinal cord axonopathy (adrenomyeloneuropathy-AMN) to severe demyelination and neuroinflammation (cerebral ALD-cALD), for which molecular mechanisms are not well known. MIN-102 (INN: leriglitazone) is a recently developed brain penetrant full PPARγ agonist which could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased ATP concentration and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long-chain fatty acids-induced toxicity simulating X-ALD. In addition, leriglitazone improved motor function, restored markers of  oxidative stress,  mitochondrial function and inflammation in spinal cord tissues from AMN mouse models and decreased the neurological disability in the EAE neuroinflammatory mouse model. X-ALD monocyte-derived patient macrophages treated with leriglitazone were less skewed towards an inflammatory phenotype and the adhesion of human X-ALD monocytes to  brain endothelial cells decreased after treatment, suggesting the potential of leriglitazone to prevent the progression to pathologically disrupted Blood-Brain Barrier. Leriglitazone increased myelin debris clearance in vitro and increased myelination and oligodendrocyte survival in demyelination-remyelination in vivo models, thus promoting remyelination. Finally, leriglitazone was clinically tested in a Phase 1 study showing CNS target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and CSF.

The results of our study support the use of leriglitazone in X-ALD and more generally in other neuroinflammatory and neurodegenerative conditions.