Friedreich’s ataxia (FRDA) is a rare autosomal recessive neurodegenerative disease characterized by progressive spinocerebellar and sensory ataxia, cardiomyopathy, diabetes mellitus and skeletal deformities. It is caused by mutations in the frataxin (FXN) gene resulting in reduced levels of frataxin, causing mitochondrial dysfunction, reduced activity of iron-sulphur cluster containing enzymes, mitochondrial iron overload, defective energy production and calcium metabolism, oxidative stress and dysregulation of mitochondrial homeostasis and biogenesis. Several studies have shown that the peroxisome-proliferator activator receptor gamma (PPARγ)/PPARγ coactivator 1 alpha (PGC1α) pathway is dysregulated in frataxin deficiency, contributing to the disease pathogenesis and supporting PPARγ as a potential therapeutic target for FRDA. Leriglitazone is a novel brain penetrant, small molecule, which selectively acts through the PPARγ.

To investigate the preclinical efficacy of a new investigational drug, leriglitazone, in preclinical models of Friedreich´s Ataxia.

Frataxin-depleted primary sensory neurons of the dorsal root ganglia (DRG) and cardiomyocytes, were used to study the effects of leriglitazone on disease-related phenotypes in vitro. FRDA patient fibroblasts and the in vivo knock-in/knock-out (KIKO) mouse model were used to validate the effect of leriglitazone on relevant mitochondrial markers. The transgenic YG8sR mice were applied to assess the effect of leriglitazone on motor function.

The data generated in the different preclinical FRDA related models showed that leriglitazone is efficacious in increasing DRG neurons survival and decreasing neurite degeneration, compensating the alterations on mitochondrial markers such as PGC1α, improving mitochondrial function, restoring energy production and calcium dysregulation, and improving global motor functions.

The preclinical results support the investigation of leriglitazone for the treatment of FRDA. Leriglitazone is currently in clinical phase 2/3 for the treatment of AMN, in phase 2 for cALD and in phase 2 for Friedreich´s Ataxia.