TLY012 Fares Well in Mouse Model as Potential Treatment for Scleroderma

TLY012 Fares Well in Mouse Model as Potential Treatment for Scleroderma

TLY012, a lab-made equivalent of a natural protein called TRAIL, can reverse skin fibrosis in mice with scleroderma by blocking important cells involved in the underlying mechanism of skin scarring, a research study found.

Targeting TRAIL pathway and this novel engineered molecule may represent a promising anti-fibrotic strategy to arrest scleroderma in humans, researchers suggest.

The study, “Targeting of dermal myofibroblasts through death receptor 5 arrests fibrosis in mouse models of scleroderma,” was published in the journal Nature Communications.

TLY012 was synthesized to mimic the activity of TRAIL, which stands for “TNF-related apoptosis-inducing ligand.” The protein, functioning as a ligand, selectively kills cells that carry specific death receptors (DR) at their surface. When TLY012 binds to a cell’s DRs, it triggers signals that will initiate a program of cell death called apoptosis.

This engineered molecule was initially developed for the treatment of cancer. While clinical studies showed that TLY012 was generally safe and well-tolerated, it failed to demonstrate its efficacy for that indication.

Seulki Lee, PhD, associate professor at Johns Hopkins University School of Medicine, and his collaborators had previously discovered that TLY012 was able to reduce liver fibrosis and cirrhosis without off-target toxicity in rat models.

Based on these findings — and as skin cells of scleroderma patients are marked by increased levels of TRAIL receptors — the team was interested in testing the therapeutic potential of TLY012 for scleroderma.

First, researchers confirmed that two TRAIL death receptors (DR4 and DR5) were highly expressed in skin samples of patients with systemic scleroderma (SSc), warranting the exploration of targeting this pathway.

Next, they assessed the ability of TLY012 to kill human skin myofibroblasts, the cells responsible for producing increased levels of collagen and other fibrotic components in the skin that support fibrosis progression. Those typesw of cells “are thought to be one of the significant originators of this disorder,” researchers said.

Their experiments showed that myofibroblasts of SSc patients are more sensitive to TLY012 because they express higher levels of DRs compared with healthy skin cells. Thus, using TLY012 was found to prevent the formation of too many of these cells, which may provide a viable therapeutic approach for scleroderma.

To further explore the anti-fibrotic efficacy of TLY012, the team tested it in a mouse model of scleroderma.

Mice were treated with TLY012 at a point in which skin fibrosis was already evident. Still, TLY012 was able to reverse skin fibrosis almost to normal skin status. The treatment reversed collagen deposition and skin thickening and reduced the number of myofibroblasts without noticeable toxicity.

Further tests confirmed that TLY012 was selectively triggering cell death in areas of fibrosis, rather than healthy tissues. In light of the prior data, the targeted cells are likely to be myofibroblasts localized to fibrotic areas.

Using genetically engineered human skin cells, researchers gained evidence that signals linked with the signaling molecule TGF-β — a critical mediator of fibrosis in various organs — would induce high levels of DRs in myofibroblasts, which in turn would make them more sensitive to TYL012 during scleroderma.

These results suggest that targeting those cells using a TRAIL-based targeted therapy, such as TYL012, may prevent or arrest scleroderma in humans. In addition, TLY012 “may have broad anti-fibrotic properties in a variety of diseases characterized by and involving myofibroblasts,” researchers said.

“Further research into combination regimens, [such as] TLY012 combined with a drug that targets different aspects of the fibrotic cascade, could also represent potent therapeutic effects,” they added.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
×
Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
Latest Posts
  • skin involvement study
  • scleroderma, racial differences
  • small airways and lung health
  • Estrogen