Intravenous allogeneic umbilical cord blood–derived mesenchymal stem cell therapy in recessive dystrophic epidermolysis bullosa patients

Abstract

BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease that causes severe mucocutaneous fragility due to mutations in COL7A1 (encoding type VII collagen [C7]). In this phase I/IIa trial, we evaluated the safety and possible clinical efficacy of intravenous infusion of allogeneic human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs) in patients with RDEB. METHODS Four adult and two pediatric patients with RDEB were treated with 3 intravenous injections of hUCB-MSCs (1 × 10 6 to 3 × 10 6 cells/kg) every 2 weeks and followed up for 8–24 months after treatment. The primary endpoint was safety. Secondary endpoints related to efficacy included clinical parameters, such as disease severity score, wound assessment, itch and pain score, and quality of life. C7 expression levels and inflammatory infiltrates in the skin, as well as serum levels of inflammatory markers and neuropeptides, were also assessed. RESULTS Intravenous hUCB-MSC infusions were well tolerated, without serious adverse events. Improvements in the Birmingham Epidermolysis Bullosa Severity Score, body surface area involvement, blister counts, pain, pruritus, and quality of life were observed with maximal effects at 56–112 days after treatment. hUCB-MSC administration induced M2 macrophage polarization and reduced mast cell infiltration in RDEB skin. Serum levels of substance P were decreased after therapy. Increased C7 expression was observed at the dermoepidermal junction in 1 of 6 patients at day 56. CONCLUSION To the best of our knowledge, this is the first clinical trial of systemic administration of allogeneic hUCB-MSCs in patients with RDEB, demonstrating safety and transient clinical benefits. TRIAL REGISTRATION ClinicalTrials.gov NCT04520022. FUNDING This work was supported by Daewoong Pharmaceutical Co. Ltd. and Kangstem Biotech Co. Ltd.

Availability of mRNA Obtained from Peripheral Blood Mononuclear Cells for Testing Mutation Consequences in Dystrophic Epidermolysis Bullosa

“…The present study also revealed that cells isolated from PBMCs using the Human Mesenchymal Stem Cell Enrichment Cocktail express type VII collagen and positive selection markers for MSCs (CD45 and CD34), suggesting that small numbers of MSCs or mesenchymal stromal cells that express type VII collagen are circulating in the peripheral blood. Although the actual function of type VII collagen-expressing MSCs and/or mesenchymal stromal cells remain unclear, it has been reported that locally injected or intravenously administered MSCs are associated with clinical improvement in patients with RDEB, with the transient restoration of type VII collagen at the basal membrane zone [16,[18][19][20][21]. These findings also support our results that MSCs can express type VII collagen.…”

Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa

“…Among other immune-modulating strategies to treat RDEB, including small-molecule agents (11) and hematopoietic progenitor cell transplantation (28), systemic administration of allogeneic mesenchymal stem cells (MSCs) has emerged as a potential, comparatively well tolerated treatment option (29)(30)(31)(32)(33). Transplanted MSCs migrate to injured tissue sites (such as RDEB skin (34,35)), where they can adaptively respond to biological signals associated with inflammation and injury (36).…”

Investigational Treatments for Epidermolysis Bullosa

“…Intravenous infusions of allogeneic MSCs from adipose tissue and umbilical cord have also been assessed in a small number of RDEB patients [99,100]. As seen in earlier trials, reduced inflammation and improved wound healing were noted.…”