Therapeutic potential of pxl065 (deuterium-stabilized r-enantiomer of pioglitazone) in hypertrophic cardiomyopathy

Background Hypertrophic Cardiomyopathy (HCM) is a genetic disorder marked by myocardial hypertrophy, fibrosis, ventricular dysfunction, arrhythmias, and an increased risk of sudden cardiac death. It is caused by mutations in sarcomere protein genes, leading to altered cell metabolism, including oxidative stress and mitochondrial dysfunction. Purpose This study evaluates the potential of the deuterium-stabilized R-enantiomer of Pioglitazone (PXL065) in modulating HCM pathogenesis. PXL065 is known to reduce inflammation, improve mitochondrial function, and restore metabolic balance. Methods We used the R719W-129SvEv/S4 HCM mouse model (R719W) to assess the effect of PXL065. Male wild type (WT) and male R719W mice were randomized at 6-8 weeks of age and treated for 10 weeks with either vehicle (regular food) or PXL065 at 60 mg/kg body weight/day mixed in food. Disease phenotype, including myocardial hypertrophy and fibrosis, was evaluated via echocardiography and histopathology. Echocardiographic measurements were analyzed by two blinded evaluators for WT (n=6), R719W (n=17), and PXL065-treated R719W (R719W + PXL065, n=12). Histopathological analysis included three sections per mouse (WT, n=8; R719W, n=18; R719W + PXL065, n=13), with 15–20 regions per section assessed by two blinded evaluators. Reactive oxygen species (ROS), transcriptome, and proteome analyses were performed to evaluate the molecular changes. Results Compared to wild-type mice, vehicle-treated R719W mice exhibited significant left ventricular hypertrophy and myocardial fibrosis, both of which were markedly reduced upon PXL065 treatment (see Figure 1 and Figure 2). The median maximum left ventricular wall thickness was 1.08 mm in WT mice, 1.39 mm in untreated R719W mice, and 1.27 mm in PXL065-treated R719W mice, representing a 8.72% reduction in the PXL065-treated R719W mice relative to untreated R719W mice (p = 0.020; see Figure 1). Similarly, the median fibrosis fraction in myocardial tissue was 0.03% in WT mice, 0.86% in R719W mice, and 0.27% in PXL065-treated R719W mice, corresponding to an 69.00% reduction in the PXL065-treated group compared to untreated R719W mice (p = 0.005; see Figure 2). The analysis of ROS, transcriptome, and proteome is still ongoing. Conclusion Preliminary analysis of this ongoing study suggests that PXL065 prevents pathological myocardial remodeling in R719W mice, including hypertrophy and fibrosis. A detailed analysis of the transcriptome and proteomics will help evaluate the mechanistic pathways of PXL065. The deuterium-stabilized R-Pioglitazone may provide a promising therapeutic approach for the treatment of HCM.