ESPE Yearbook of Paediatric Endocrinology

Sci Transl Med. 2021; 13(596): eabc0555. PMID: 34078742https://pubmed.ncbi.nlm.nih.gov/34078742/

Brief Summary: These in vitro and in vivo studies show that the brain penetrant PPARγ agonist leriglitazone restores multiple biological pathways relevant for neuroinflammatory and neurodegenerative diseases, and particularly for X-linked adreno-leukodystrophy (X-ALD).

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists act on multiple pathways through gene activation or repression, and have the capacity to induce neuroprotective and restorative effects in several preclinical models of neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Parkinson’s disease, Friedreich’s ataxia, Alzheimer’s disease and adrenomyeloneuropathy (AMN) (1). Leriglitazone is a PPARγ agonist developed by Minoryx Therapeutics for the treatment of X-ALD and other neurodegenerative diseases due to its blood-brain-barrier (BBB) penetration, good bioavailability and safety profile (2). Leriglitazone, also known as MIN-102, is the hydrochloride salt of the active metabolite M4 (M-IV) of pioglitazone (Actos, Takeda).

These authors performed several experiments in rodent primary neurons, astrocytes, endothelial cells, oligodendrocytes and microglia. Leriglitazone efficacy in treating X-ALD was further validated in vivo in murine AMN models and in mice with Experimental Autoimmune Encephalomyelitis (EAE), a surrogate model for the neuroinflammatory component of cerebral adrenoleukodystrophy (cALD). To better understand the mode of action of leriglitazone in potentially preventing early stages of the development of cALD, the authors used in vitro models and showed a 50% increase in the brain/plasma exposure ratio compared to pioglitazone in mice, while the unbound fraction of leriglitazone in brain also increased to 9.1 and 13.6% compared to 1.6 and 1.2% of pioglitazone. The authors further showed protective effects of leriglitazone from VLCFA-induced toxicity in an in vitro model simulating X-ALD, in mouse models of AMN. In models of blood-brain barrier mimicking X-ALD conditions, by challenging the brain endothelium/astrocytes with an inflammatory stimulus, or in monocytes/macrophages derived from patients with X-ALD, they showed anti-inflammatory effects of leriglitazone. Furthermore, the protective effects of leriglitazone against demyelination and/or enhancement of remyelination in vitro and in vivo. Finally, a Phase I pharmacodynamic/pharmacokinetic study in healthy volunteers was completed to confirm inflammatory biomarker changes and target engagement in plasma and CSF in humans at concentrations corresponding to preclinical efficacious doses.

This is an important study, highlighting the potential of leriglitazone, particularly as no effective pharmacological treatments are currently available for X-ALD. Hematopoietic Stem Cell Transplantation (HSCT) or experimental gene therapy can be used to arrest the cerebral form of X-ALD by counteracting activated microglia with differentiated new macrophages/microglia from hematopoietic stem cells. However, delay in diagnosis, lack of appropriate donors and adverse events associated with transplantation make HSCT only available and effective to a minority of patients with cALD. In addition, HSCT does not avoid the progression to AMN in a later stage.

References: 1. Lin X, Meng X, Song Z, Lin J. Peroxisome proliferator-activator receptor γ and psoriasis, molecular and cellular biochemistry. Mol Cell Biochem. 2022 Jul;477(7):1905–1920. 2. Rodríguez-Pascau L, Britti E, Calap-Quintana P, Dong YN, Vergara C, Delaspre F, Medina-Carbonero M, Tamarit J, Pallardó FV, Gonzalez-Cabo P, Ros J, Lynch DR, Martinell M, Pizcueta P. PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia. Neurobiol Dis. 2021; 148: 105–162.