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Spatial Proteomics Method Helps Solidify Severe Skin Disease Treatment Strategy

NEW YORK – With the help of detailed proteomic analyses, an international team has linked a serious skin condition to enhanced levels of inflammatory JAK/STAT pathway activation, highlighting the possibility of developing a JAK inhibitor-based treatment for it.

The work, published in Nature on Wednesday, focused on "toxic epidermal necrolysis" (TEN), a sometimes-fatal condition characterized by keratinocyte cell death and subsequent skin epidermal detachment in response to common medications such as antibiotics.

"Despite the severity of the disease and its significant mortality rate, its molecular mechanisms remained poorly understood until now," first author Thierry Nordmann, with the Max Planck Institute of Biochemistry, the University Hospital Zurich, and the Ludwig Maximilian University Munich, and senior author Matthias Mann, at the Max Planck Institute of Biochemistry and the University of Copenhagen, said in an email.

They noted that the condition can lead to long-term complications ranging from skin pigmentation or scarring to vision problems and psychological distress, underlining the importance of pursuing treatments for tackling the roots of the condition rather than supporting affected individuals through their symptoms.

For their study, Mann, Nordmann, and colleagues used a single-cell proteomics approach called "deep visual proteomics" (DVP), described in a Nature Biotechnology paper in 2022, to retrospectively characterize protein patterns at the cell type level in formalin-fixed paraffin-embedded skin samples from healthy control individuals or individuals with mild or severe forms of "cutaneous adverse drug reactions" (CADR).

The CADR group included individuals affected by TEN, as well as those with other adverse drug reactions: a relatively mild and self-resolving condition called maculopapular rash (MPR) and a rare, severe condition known as "drug reaction with eosinophilia and systemic symptoms" (DRESS).

"These proteomic analyses across all major types of cutaneous drug reactions with cell-type resolution provided insights into the molecular mechanism of each CADR that we leveraged for therapeutic interventions," the authors explained.

Using DVP to quantify some 5,000 proteins in keratinocyte and skin-infiltrating immune cells in the samples, the team unearthed cell type-specific protein shifts that distinguished the CADR conditions from one another and from samples representing healthy controls — including epigenetic regulatory shifts in skin-infiltrating immune cells from DRESS samples and higher-than-usual JAK/STAT pathway activity in TEN keratinocytes and immune cells.

Along with follow-up experiments using targeted transcriptomics to back up proteomic findings for the CADR conditions, the team delved into the available spatial clues to pinpoint keratinocyte cell inflammation at locations at or around epidermal detachment sites in TEN cases.

"This spatial proteomics approach revealed a striking hyperactivation of the inflammatory JAK/STAT pathway in TEN patients, which we hadn't known before," Mann and Nordmann said, arguing that the "implications of these proteomics findings for understanding, preventing, and treating such skin conditions in the future are profound."

On the other hand, cytotoxic features were curbed in keratinocyte cells isolated from TEN survivors and treated in vitro with a pan-JAK inhibitor known as tofacitinib. Similarly, the team's mouse model experiments revealed reduced TEN symptom severity after treatment with tofacitinib or more targeted JAK1 inhibitors.

Most promisingly, the researchers saw re-epithelialization of affected cutaneous tissue in seven TEN patients treated with such JAK inhibitors, supporting the notion that short-term JAK inhibitor treatment may prove effective for curbing TEN-related mortality.

"Looking ahead, we believe this research paves the way for clinical trials of JAK inhibitors in TEN, addressing one of the most serious unmet needs in dermatology," Mann and Nordmann said, adding that a similar strategy may help in understanding and potentially treating other serious conditions in the future.

"This approach could be applied to other complex skin conditions and diseases in other organs, potentially accelerating drug discovery across multiple fields of medicine," they noted, adding that the approach "also opens up new opportunities for drug repurposing, which is particularly valuable for rare and severe conditions."