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Background Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis caused by biallelic COL7A1 mutations, where chronic inflammation drives disabling complications affecting quality of life and survival. Effective inflammatory control remains a major unmet need. While systemic administration of mesenchymal stromal cells (MSC) from various sources has proven safe with transient benefits yet only one recent placebo-controlled study in RDEB. Consistent type VII collagen (C7) deposition is lacking, and therapeutic mechanisms and predictive biomarkers remain undefined. The MesenSistem-EB trial evaluated for the first time the use of haploidentical BM-MSC and extensively explored their anti-inflammatory potential as a monotherapy in RDEB. Methods Phase I/II, single-center, open-label trial, in which nine children with severe RDEB were recruited and eight completed the study after three intravenous infusions of haploidentical BM-MSC (2–3×10 6 cells/kg) at 21-day intervals. Safety, clinical and patient-reported outcomes, systemic inflammatory mediators and peripheral blood immune profiles were assessed over 12 months. Results MSC therapy was well-tolerated without serious adverse events. Long-term pruritus, sleep and fatigue were globally reduced. In 7/8 patients at least one key domain significantly improved (disease severity, pruritus, or inflammation) with five classified as good responders. Global median CRP and fibrinogen levels remained stable throughout the study period. Responses correlated with sCD40L and MCP1 dynamics. Flow cytometry revealed altered circulating myeloid and lymphoid compartments at baseline. Post-infusion, immune cell subset changes did not consistently distinguish responders while typically including increased CLA expression on monocytes, partial recovery of memory CD8 + T cells and disappearance of an aberrant granulocyte population, potentially linked to immature myeloid mobilization driven by chronic inflammation. Haploidentical MSC did not consistently confer durable engraftment or sustained C7 deposition. Conclusions BM-MSC is a safe and potentially effective anti-inflammatory intervention that mitigates the expected escalation of systemic inflammatory markers during a critical phase of RDEB progression. MCP1 and sCD40L modulation, with both potentially serving as predictive biomarkers. MSC appear to exert both shared and patient-specific immunomodulatory effects depending on baseline inflammatory cues. Findings provide insights into individual variability, underlying mechanisms and potential therapeutic responsiveness, supporting their use also as a complementary strategy. Clinical trial registration ClinicalTrials.gov , identifier NCT04153630.
Maseda et al. (Tue,) studied this question.