LYTAC Therapy Targets Root Cause of Diabetic Foot Ulcers by Removing Excess Inflammatory Proteins
核心洞察
The EU-funded APTADEGRAD project has developed lysosome-targeting chimeras (LYTACs) that remove excess inflammatory proteins rather than merely blocking them, offering a potential disease-modifying therapy for diabetic foot ulcers (搜索).
Diabetic foot ulcers (搜索) affect roughly a quarter of the more than 800 million people with diabetes (搜索) worldwide, with a mortality rate of about 5% within one year and 42% within five years.
In diabetic wound models, the compounds reduce inflammation and accelerate healing, performing as well as or better than antibody-based approaches targeting the same proteins.
EU-backed researchers have developed a groundbreaking therapy for diabetic foot ulcers (搜索) that targets the runaway inflammation preventing these chronic wounds from healing. The APTADEGRAD project, led by Spanish biotechnology company Lincbiotech (搜索), has created a new class of compounds called lysosome-targeting chimeras, or LYTACs, that remove excess inflammatory proteins from the wound environment rather than simply blocking them.
Diabetic foot ulcers (搜索) are among the most challenging complications of diabetes (搜索), a disease affecting more than 800 million people worldwide. "Diabetes is a very complex disease, causing a number of serious complications that affect patients' lives in many ways," said Juan Ruiz-Constantino, CEO of Lincbiotech (搜索). "One of the most complex is diabetic foot ulcers."
Around a quarter of people with diabetes (搜索) will develop a foot ulcer at some point, according to APTADEGRAD's project data, and a significant proportion will result in some form of amputation. The mortality burden is striking: roughly 5% of patients die within a year of developing a diabetic foot ulcer, rising to 42% after five years. The economic toll is equally severe, with Germany alone carrying out an estimated 34,500 diabetes-related amputations every year, while diabetic foot ulcers (搜索) and amputations cost the UK's National Health Service the equivalent of EUR 1.1 billion annually.
Despite the scale of the problem, no approved therapy directly addresses the disease mechanisms driving diabetic foot ulcers (搜索). "You are treating the symptoms, but you don't have an approved drug for a disease-modifying approach," explained Ruiz-Constantino.
Why Diabetic Wounds Resist Healing
A key challenge with diabetes (搜索) is peripheral nerve damage and impaired blood circulation. Damaged nerves mean wounds on the feet can initially go unnoticed, while poor circulation hinders healing. Inflammation normally helps fight infection and coordinate tissue repair, but in diabetic wounds, inflammatory molecules can build up to excessive levels, preventing the wound from progressing through the normal healing process.
The researchers have identified several important drivers of this response, including proteins known as IL-1β (搜索), its receptor IL-1R1 (搜索), and MMP-9 (搜索). Rather than blocking these proteins altogether, the team aims to remove excess amounts of them.
Harnessing the Cell's Recycling System
The solution relies on lysosomes, tiny structures inside cells that act as the body's recycling system. "The lysosomes are part of the quality control system we have inside our cells," Ruiz-Constantino explained. The approach captures proteins outside the cell, transports them inside, and sends them to this cellular recycling system, restoring healthier protein levels and a more balanced inflammatory response.
To activate this waste removal process, the team developed LYTACs, which work like miniature delivery systems. One end captures an inflammatory protein, while the other binds to receptors on the cell surface, prompting the cell to pull the entire complex inside and send it to the lysosome for destruction. This allows researchers to reduce protein levels in a controlled way rather than eliminate them completely, maintaining enough of the proteins to support healing while preventing the excessive inflammatory response that keeps wounds open.
A Distinct Mechanism from Antibody Therapies
In diseases such as rheumatoid arthritis, psoriasis and Crohn's disease, monoclonal antibody therapies have transformed treatment by blocking inflammatory proteins. Similar approaches have been explored for diabetic wounds, but with limited success.
"Antibodies bind to and block a protein, but they don't remove it from the environment. The APTADEGRAD approach does actually remove that protein from the environment, and this is what we think will be more beneficial for tackling the wound inflammation," explained Dr Holly Wilkinson, a wound healing specialist at the University of Hull, UK, who has been helping to evaluate the technology.
Once the chimera has done its job, the whole complex, drug and protein together, is broken down inside the cell, which should also reduce the risk of side effects. This is particularly important in patients with complex illnesses such as diabetes (搜索).
Promising Early Results
The results so far are encouraging. In diabetic wound models, the compounds reduce inflammation and accelerate healing, and in many cases perform as well as or better than antibody-based approaches targeting the same proteins.
"We see that the treatments accelerate wound healing and dampen inflammation," Wilkinson said. "A lot of the time we see effects that are as good as or better than antibody treatments."
The trials have so far focused on injections administered under the skin near ulcers, but the team has also developed a hydrogel formulation that can be applied directly to wounds, allowing the medicine to be released gradually over time. Both approaches are designed to maximise local effects while minimising unwanted side effects elsewhere in the body.
Wider Implications and Next Steps
Although diabetic foot ulcers (搜索) remain the immediate focus, the possibilities could extend much further. If successful, the technology could eventually be adapted to treat other chronic wounds and inflammatory diseases, while also providing some of the first real-world evidence for the broader medical potential of LYTAC-based therapies.
The next step will be generating enough evidence on safety and effectiveness to support the first human clinical trials, which Wilkinson hopes could begin around 2030. "If we could get something into the clinic that demonstrates effectiveness at healing diabetic wounds, it would be absolutely game changing," she said.
For millions of people living with diabetes (搜索), a treatment that tackles the root causes of these wounds rather than simply managing their consequences could represent a long-awaited breakthrough. The APTADEGRAD project is due to run until the end of 2027, with researchers from Belgium, Portugal, Spain and the UK collaborating on the effort.