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

ABSTRACT: BACKGROUNDRecessive 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.METHODSFour adult and two pediatric patients with RDEB were treated with 3 intravenous injections of hUCB-MSCs (1 × 106 to 3 × 106 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.RESULTSIntravenous 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.CONCLUSIONTo 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 REGISTRATIONClinicalTrials.gov NCT04520022.FUNDINGThis work was supported by Daewoong Pharmaceutical Co. Ltd. and Kangstem Biotech Co. Ltd.

SUBMITTER: Lee SE

PROVIDER: S-EPMC7934866 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Lee Sang Eun SE Lee Seung-Ju SJ Kim Song-Ee SE Kim Kinam K Cho Boyoung B Roh Kyounghwan K Kim Soo-Chan SC

JCI insight 20210125 2

BACKGROUNDRecessive 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.METHODSFour adult and two pediatric patients with RDEB were treated with 3 intravenous injections o ...[more]

PMID: 33491668

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Project description: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.

Project description:BackgroundRecessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL7A1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans.MethodsBetween October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize anchoring fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography.ResultsOne patient died of cardiomyopathy before transplantation. Of the remaining six patients, one had severe regimen-related cutaneous toxicity, with all having improved wound healing and a reduction in blister formation between 30 and 130 days after transplantation. We observed increased C7 deposition at the dermal-epidermal junction in five of the six recipients, albeit without normalization of anchoring fibrils. Five recipients were alive 130 to 799 days after transplantation; one died at 183 days as a consequence of graft rejection and infection. The six recipients had substantial proportions of donor cells in the skin, and none had detectable anti-C7 antibodies.ConclusionsIncreased C7 deposition and a sustained presence of donor cells were found in the skin of children with recessive dystrophic epidermolysis bullosa after allogeneic bone marrow transplantation. Further studies are needed to assess the long-term risks and benefits of such therapy in patients with this disorder. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00478244.)

Project description:BackgroundRevertant mosaicism has been described previously in recessive dystrophic epidermolysis bullosa (RDEB), manifesting as regions of skin with normal mechanical and biological characteristics. Here we report the discovery of revertant dermal fibroblasts, unique in that all other documented cases of revertant mosaicism occur in epidermal keratinocytes.ObjectivesTo determine the cause of revertant mosaicism found in a patient with RDEB from isolated epidermal keratinocytes and dermal fibroblasts in blister and mosaic skin regions.MethodsSkin biopsies were taken from blister and mosaic skin regions of a patient with RDEB. Allele identification was confirmed and the type VII collagen (C7) content and COL7A1 expression profile of isolated keratinocytes and fibroblasts was determined.ResultsKeratinocytes isolated from the mosaic area had a slight increase in C7, although overall expression of COL7A1 was unchanged between blister and mosaic fibroblasts. Differential allele expression was identified in blister and mosaic fibroblasts using targeted RNA sequencing (TREx), where the allele harbouring a point mutation was preferentially expressed over that containing a frameshift mutation. A crossing over event was identified in mosaic fibroblasts that was not present in blister fibroblasts, yielding a functional COL7A1 allele in a subset of cells.ConclusionsIn documenting a novel case of revertant mosaicism in RDEB, we have identified dermal fibroblasts as having the capacity to correct blistering functionally. We have also pioneered the use of TREx in quantifying allele-specific expression. Using fibroblasts instead of keratinocytes for RDEB therapies offers advantages in the local and systemic therapy of RDEB. What's already known about this topic? Revertant mosaicism has been previously documented in patients with recessive dystrophic epidermolysis bullosa (RDEB), however, it has only been found in epidermal keratinocytes. What does this study add? We have demonstrated that COL7A1 gene reversion in dermal fibroblasts occurs and is able to form functional skin in a patient with RDEB. Additionally, we have pioneered a new application for targeted RNA sequencing in quantifying allele-specific expression in fibroblasts and keratinocytes. What is the translational message? This opens up possibilities for using fibroblasts as local and systemic therapy for patients with RDEB.

Project description:Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.

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

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

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