TAK242 Prevents and Reverses Fibrosis in Mice, Could Be Potential Scleroderma Therapy, Study Suggests
Inhibiting a key innate immunity protein known as TLR4 with a compound called TAK242 prevented and reversed skin and lung fibrosis (scarring) in mouse models, and eased the production of collagen in cells from scleroderma patients.
The findings suggest that TAK242 may be a new therapeutic approach for people with scleroderma.
The research, “Pharmacological Inhibition of Toll-Like Receptor-4 Signaling by TAK242 Prevents and Induces Regression of Experimental Organ Fibrosis,” was published in the journal Frontiers in Immunology.
Scleroderma is characterized by fibrosis in multiple organs. Despite advances in understanding cellular processes implicated in scleroderma development, there is still scarce evidence of why these processes become deregulated in inflammation and fibrosis.
Levels of TLR4 (a protein of the immune system) and its ligands, called damage-associated molecule patterns (DAMPs), are higher in the skin and lungs of scleroderma patients. Prior work showed that inhibiting TLR4 prevented and reversed organ fibrosis in several mouse models. In contrast, stimulation of TLR4 in fibroblasts — cells that release collagen during the development of fibrosis — was associated with remodeling of the extracellular matrix, which provides structural and biochemical support to cells and drives fibrosis.
TAK242 is a small molecule inhibitor of TLR4 that blocks production of the inflammatory mediators TNF-alpha, interleukin (IL)-1, and IL-6.
Given the prior findings that TLR4 and DAMPs drive fibroblasts’ activation in scleroderma, the study — partially funded by Takeda Pharmaceutical, TAK242’s developer — evaluated the effect of TAK242 in mouse models of fibrosis and in fibroblasts collected from patients with scleroderma or from mice.
First, TAK242 (10 or 30 mg/kg of body weight) was administered to mice, together with the fibrosis-inducing compound bleomycin, five days a week for two weeks.
Results showed a marked reduction of skin thickness and accumulated collagen in mice with skin fibrosis. Furthermore, TAK242 reduced levels of several pro-fibrotic mediators and of the fibroblast marker alpha-SMA.
The team also showed that administering TAK242 when skin fibrosis was already established led to reduced dermal thickness and reduced levels of hydroxyproline, a component of collagen. In the lung, the experimental therapy eased the influx of inflammatory cells, the presence of fibrotic lesions, and collagen accumulation.
In an inflammation-independent model of fibrosis, six-week treatment with TAK242 also lessened skin thickening and did not cause adverse effects.
Subsequent experiments in a model of peritoneal fibrosis (fibrosis in the peritoneal cavity, the space within the abdomen that contains the intestines, stomach, and liver) showed that TAK242 was highly effective in preventing fibrosis, including a reduction of over 60% in membrane thickness, and attenuated activity of fibrotic and inflammatory genes.
TAK242 also reduced collagen and alpha-SMA levels in cultures of mouse fibroblasts. Cultures with cells derived from four scleroderma patients also showed that a 24-hour treatment with the investigational compound lowered collagen gene activity and alpha-SMA levels.
“Altogether, these findings identify TAK242 as an anti-fibrotic agent in preclinical models of organ fibrosis,” the scientists stated. “TAK242 might potentially represent a novel strategy for the treatment of [scleroderma] and other fibrotic diseases.”