Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis

Abstract

BackgroundThe pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic targets.ObjectiveTo determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis.MethodsThe antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing.ResultsLow levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3—intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways.ConclusionsThese findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

“…Surprisingly, none of the single agonists inhibited TGF‐β1‐induced fibrotic gene expression, yet it was completely blocked by IVA337. Our previous work supports that inhibition of TGF‐β1‐induced myofibroblast transdifferentiation by IVA337 is mediated through inhibition of phospho‐SMAD2/3 expression 41. Thus, IVA337 with pan‐PPAR ligand‐binding potency consistently inhibits hHSC proliferation, culture‐mediated activation, and TGF‐β1‐driven profibrotic activation and prevents fibrosis and fibrosis progression in vivo .…”

Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension

“…In addition, IVA337 reduced the α-SMA expression in HPF cells induced by TGF-β. This finding is consistent with the reduction of the TGF-β-induced α-SMA expression observed with IVA337 in dermal fibroblasts3 and with rosiglitazone in MRC-5 cells 30. Moreover, potent attenuation of TGF-β-induced collagen protein production has been observed on treatment with PPARγ agonists in human lung fibroblasts 31…”

“…Indeed, IVA337 restores the expression of PPAR isoforms in lesional lung fibroblasts from mice challenged with bleomycin and Fra-2 transgenic mice (online supplementary figure S9) and reduces TGF-β-induced canonical and non-canonical cascades in human fibroblasts 3. IVA337 also inhibits TGF-β induced collagen synthesis in dermal fibroblasts3 and directly interferes with primary HPF, the effector cells of pulmonary fibrosis. In the present study, IVA337 inhibited HPF proliferation induced by PDGF in a concentration dependent manner.…”

Translating Autoimmune Pathogenesis into Targeted Therapies for Systemic Sclerosis

“…The pan-peroxisome proliferator-activated receptor (PPAR) agonist, IVA337, is currently being investigated in a phase II randomised, controlled study of patients with dcSSc [120]. The anti-fibrotic properties of PPAR agonists are supported by the results of a recent study in a mouse model of dermal fibrosis, in which IVA337 administration produced reductions in extracellular matrix deposition and several biomarkers of inflammation and fibrosis [121]. Also promising is the ongoing phase III study of nintedanib in patients with SSc-ILD [122].…”