Research ArticleNEURODEGENERATIVE DISORDERS

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

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Science Translational Medicine  02 Jun 2021:
Vol. 13, Issue 596, eabc0555
DOI: 10.1126/scitranslmed.abc0555

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A drug candidate for X-ALD

Therapies for treating the neurodegenerative disease X-linked adrenoleukodystrophy (X-ALD) are lacking. Patients often develop total disabilities and have reduced life expectancy. Peroxisome proliferator–activated receptor gamma (PPARγ) agonists had therapeutic effects in models of neurodgenerative diseases. Here, Rodriguez-Pascau et al. tested the brain penetrant full PPARγ agonist leriglitazone in preclinical models of X-ALD and in a phase 1 clinical trial. The treatment neuroprotective effects reduced neuroinflammation and improved mitochondrial functions in rodent- and patient-derived cells. In vivo, the treatment improved motor symptoms in X-ALD mice. Target engagement and modulation of inflammatory markers were reported in patients, suggesting that leriglitazone might be an effective treatment for X-ALD.

Abstract

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. Leriglitazone is a recently developed brain penetrant full PPARγ agonist that could modulate multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-ALD. We found that leriglitazone decreased oxidative stress, increased adenosine 5′-triphosphate concentration, and exerted neuroprotective effects in primary rodent neurons and astrocytes after very long chain fatty acid–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 toward 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. Last, leriglitazone was clinically tested in a phase 1 study showing central nervous system target engagement (adiponectin increase) and changes on inflammatory biomarkers in plasma and cerebrospinal fluid. The results of our study support the use of leriglitazone in X-ALD and, more generally, in other neuroinflammatory and neurodegenerative conditions.

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