Groundbreaking technology paves the way for life-saving treatment for fatal skin reaction

Enlarge

An international team of researchers led by Professor Matthias Mann from the Max Planck Institute of Biochemistry (MPIB) in Martinsried and Professor Lars French from LMU Klinikum München has made a groundbreaking discovery that could save the lives of patients with toxic epidermal necrolysis (TEN). TEN is a rare but often fatal side effect of common medications that leads to extensive skin detachment. Using innovative spatial proteomics, one of the most advanced molecular biology techniques, the team was able to identify the inflammatory JAK/STAT signaling pathway as the main cause of the disease. After testing their results in preclinical models, the experts successfully treated the first seven patients worldwide with JAK inhibitors. All patients recovered quickly and completely. This groundbreaking study was published in the journal Nature.

In the current study, researchers used spatial proteomics to analyze skin samples from TEN patients. This cutting-edge approach, known as Deep Visual Proteomics (DVP), combines powerful microscopy with AI-driven analysis, laser-guided microdissection and finally highly sensitive mass spectrometry. The scientists examined individual cells and created a map of thousands of proteins that drive this deadly reaction.

Proteomics shifts the paradigm

Dr. Thierry Nordmann, first author and scientist at the MPIB and senior physician in the Department of Dermatology and Allergology at the LMU Klinikum explains: "By applying spatial proteomics to archived patient samples with TEN, we were able to precisely isolate and analyze individual cell types to understand what is actually happening in the patients' skin. We found a striking overactivation of the pro-inflammatory JAK/STAT signaling pathway and thus found a way to intervene with JAK inhibitors in this deadly disease. JAK inhibitors are a class of drugs that are already used to treat other inflammatory diseases such as atopic dermatitis or rheumatoid arthritis."

TEN is a rare but extremely serious side effect of common medications such as allopurinol (a drug used to treat gout) or certain antibiotics. TEN causes extensive blistering and peeling of the skin. With a mortality rate of up to 30 percent, the seemingly harmless rash quickly develops into a life-threatening disease. Until now, there has been no effective therapy for TEN and treatment has mainly been limited to supportive measures, such as relieving pain and preventing infection.

The team analyzed the results using a series of preclinical studies, including in vitro models and two different mouse models. The results of the research collaboration between scientists in six countries were consistent and overwhelmingly positive: JAK inhibitors show real potential in the treatment of this devastating disease.

A new therapy on the horizon for TEN patients

In collaboration with clinical teams led by Professor Ji at the First Affiliated Hospital of Fujian Medical University in China, the research team administered JAK inhibitors to patients suffering from TEN. Remarkably, all seven patients treated showed rapid improvement and full recovery.

Professor French, co-corresponding author and Chair of Dermatology at LMU Munich, explains: "The new evidence that inhibition of the JAK/STAT pathway has the potential to reduce the high mortality of this severe cutaneous drug reaction paves the way for clinical trials to approve JAK inhibitors to address one of the most significant untreatable medical problems to date."

Although larger clinical trials are needed to confirm the efficacy and safety of JAK inhibitors in TEN, the new findings offer a promising approach for future treatment of patients suffering from TEN. The study also points to new possibilities for the alternative use and development of drugs. The Max Planck Society, together with the Ludwig-Maximilians-University, has filed a patent application for the use of JAK inhibitors for the treatment of TEN and related diseases.

Matthias Mann from MPIB summarizes: "Our results not only open up new ways to treat TEN, but also highlight the potential of spatial proteomics to drive medical breakthroughs. To our knowledge, this is the first time that a spatial omics technology has had an immediate and tangible impact in the clinic by identifying a treatment that has already changed people's lives for the better. This approach could be applied to a wide range of diseases and potentially accelerate drug discovery in many areas of medicine."

Nordmann, T.M., Anderton, H., Hasegawa, A. et al. Spatial proteomics identifies JAKi as treatment for a lethal skin disease. Nature (2024).