Systemic Sclerosis Study Finds Wnt Signaling a Promising Therapeutic Target

A review into Wnt pathway signaling as a potential target for systemic sclerosis treatment is optimistic regarding the current status of research and development in the field. The review, “Canonical Wnt signaling in systemic sclerosis,“ was published in the journal Laboratory Investigation by Christina Bergmann and Jörg HW Distler from the University of Erlangen-Nuremberg, Germany.

Although the causes of systemic sclerosis (SSc) have not been identified, prolonged activation of fibroblasts secreting extracellular matrix proteins such as collagen are known contributors to disease development. Several mechanisms of fibroblast activation have been proposed, and several studies suggest that Wnt signaling is an important mediator of fibroblast activation.

There are two possible pathways for Wnt signaling, and the canonical one — dependent on the factor β-cathenin — is involved in fibrosis development. The activation of this pathway can be regulated at several levels. Endogenous blockers of the pathway, such as DKK1 and SFRP1, are known, as are Tankyrases — substances that stabilize β-cathenin.

In fibroblasts isolated from SSc patients, increased expression of Wnt proteins along with decreased expression of endogenous Wnt antagonists such as DKK1 and SFRP1 have been reported. Also, nuclear accumulation of β-cathenin occurs in fibrotic skin from systemic sclerosis patients.

In experimental studies, Wnt signaling and overexpression of β-cathenin activate fibroblasts, leading to dermal fibrosis in laboratory animals.

The inflammatory and profibrotic cytokine TGF-β also induces signaling through the pathway and promotes fibrosis in experimental animals by inhibiting the expression of DKK1 and SFRP1. Blocking the TGF-β receptor was shown to decrease Wnt signaling. Interestingly, studies suggested that Wnt and TGF-β signaling might be reinforcing each other to persistently drive fibroblast activation.

Genetic proof-of-concept studies have shown the potential of targeting Wnt signaling in the development of treatments for systemic fibrosis and other fibrotic disorders. Development of pharmacological solutions has, however, been lagging.

Canonical Wnt signaling was long considered “undruggable” due to the pathway’s lack of classical pharmacological targets. But several pharmacological approaches inhibiting Wnt signaling have recently been developed, and some of these drugs have already reached clinical trials. One, PRI-724, which targets β-cathenin, was evaluated in a Phase I trial as a seven-day treatment in patients with solid tumors, and showed an acceptable toxicity profile. Phase 1/2 studies of this drug are ongoing.

Tankyrase inhibitors may also have therapeutic potential. Treatment with XAV939, a selective tankyrase inhibitor, reduced the activation of cultured fibroblasts and prevented experimentally induced skin fibrosis.

Moreover, inhibitors of DNA methylation have been shown to increase DKK1 and SFRP1 signaling, resulting in the Wnt pathway’s suppression. These inhibitors also have demonstrated antifibrotic effects in experimental models. While DNA methylation is a non-specific process modulating numerous pathways, the authors argue for the inhibitors’ high translational potential. Methylation inhibitors have already been approved for the treatment of hematological cancers, and they might be an option for fibrotic diseases before Wnt pathway modulators reach clinical trials.

One concern of pathway targeting in a chronic disease such as systemic sclerosis is that Wnt signaling is involved in adult stem cell maintenance. Inhibition of the pathway could result in toxicity. Tissues with a rapid cellular growth, such as the intestine, are particularly vulnerable to such treatments.

In contrast to genetic downregulation of the pathway, pharmacological inhibition of Wnt signaling in mice is seen to be well-tolerated, with no overt gastrointestinal toxicity. Scientists believe that this is because pharmacological inhibitors — unlike genetic modifications — cannot completely suppress the pathway. The low level of remaining activity may be enough to protect against toxicity.

These studies were, however, performed in a time frame much shorter than that needed to manage a chronic disease like fibrosis. Potential hindrances might be overcome, at least in part, by employing combination therapies. More research is required, the authors conclude, to assess possible adverse effects and limit potential toxicity of long-term treatment with candidate Wnt inhibitors.