Abstract
BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder that comes about due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5+ dermal mesenchymal stem cells (ABCB5+ MSCs) possess immunomodulatory, inflammation-dampening, and tissue-healing capacities. In a Col7a1–/– mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals’ lifespans.METHODSIn this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4–36 years) enrolled into 4 age cohorts received 3 i.v. infusions of 2 × 106 ABCB5+ MSCs/kg on days 0, 17, and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety.RESULTSAt 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%–30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB‑c) score of 18.2% (1.9%–39.8%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%–42.9%; P = 0.033) and 25.0% (–8.4% to 46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product: 1 mild lymphadenopathy and 2 hypersensitivity reactions. The latter 2 were serious but resolved without sequelae shortly after withdrawal of treatment.CONCLUSIONThis trial demonstrates good tolerability, manageable safety, and potential efficacy of i.v. ABCB5+ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation.TRIAL REGISTRATIONClinicaltrials.gov NCT03529877; EudraCT 2018-001009-98.FUNDINGThe trial was sponsored by RHEACELL GmbH & Co. KG. Contributions by NYF and MHF to this work were supported by the NIH/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.
Highlights
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and lifethreatening inherited skin fragility disorder
At 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%-30%; p=0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician score of 18.2% (1.9%-39.8%; p=0.037) were observed
While gene correction-based therapy approaches have shown promising, albeit variable, first results in small early-phase clinical trials [16,17,18], such therapies are associated with complex challenges relating to technological issues, oncogenic potential, immune reactions and maintenance of the therapeutic effect [12, 14, 15]
Summary
Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and lifethreatening inherited skin fragility disorder. While gene correction-based therapy approaches have shown promising, albeit variable, first results in small early-phase clinical trials [16,17,18], such therapies are associated with complex challenges relating to technological issues, oncogenic potential, immune reactions and maintenance of the therapeutic effect [12, 14, 15] It is unclear how quickly curative EB treatments can be implemented in clinical routine care [12, 19, 20]. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder due to a lack of functional type VII collagen, for which no effective therapy exists. In a Col7a1–/– mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals’ lifespans
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