ABCB5+ Dermal Mesenchymal Stromal Cells with Favorable Skin Homing and Local Immunomodulation for Recessive Dystrophic Epidermolysis Bullosa Treatment

Riedl, Julia; Pickett‐Leonard, Michael; Eide, Cindy R.; Kluth, Mark A.; Ganss, Christoph; Frank, Natasha Y.; Frank, Markus H.; Ebens, Christen L.; Tolar, Jakub

doi:10.1002/stem.3356

Cited by 23 publications

(22 citation statements)

References 30 publications

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“…Furthermore, beyond potential disease activity-related improvements, it might be anticipated that repeated doses given over a longer period of time could, by decreasing disease activity, reduce further damage accumulation. Interestingly, very recently it was shown that ABCB5 + MSCs possess a superior homing potential to injured tissues compared to bone marrow-derived MSCs, presumably due to increased HOXA3 gene expression, and are capable of secreting type VII collagen (76). Thus, it might be speculated that long-term treatment with ABCB5 + MSCs, beyond alleviating disease activity, could even enhance skin and mucosal structural integrity via accumulated deposition of type VII collagen.…”

Section: Discussionmentioning

confidence: 99%

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

Kiritsi¹,

Dieter²,

Niebergall-Roth³

et al. 2021

JCI Insight

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Background. 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. ABCB5-positive 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.Methods. In this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4-36 years) enrolled into four age cohorts received three intravenous infusions of 2×10 6 ABCB5 + MSCs/kg on days 0, 17 and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety. Results. At 12 weeks, statistically significant median (IQR) reductions in the EpidermolysisBullosa 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%-46.4%; p=0.168), respectively. Three adverse events were considered related to the cell product, one mild lymphadenopathy and two hypersensitivity reactions. The latter two were serious but resolved without sequelae shortly after withdrawal of treatment. Conclusion.This trial demonstrates good tolerability, manageable safety and potential efficacy of intravenous ABCB5 + MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

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

Kiritsi¹,

Dieter²,

Niebergall-Roth³

et al. 2021

JCI Insight

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“…A small subpopulation of mesodermal skin cells manifesting MSC features has been recently identified ( Riedl et al, 2021 ). These cells express the ATP-binding cassette subfamily B member 5 (ABCB5+ MSCs).…”

Section: Innovative Therapies For Diabetic Foot Ulcersmentioning

confidence: 99%

Innovative Cell and Platelet Rich Plasma Therapies for Diabetic Foot Ulcer Treatment: The Allogeneic Approach

Mastrogiacomo

Nardini

Collina

et al. 2022

Front. Bioeng. Biotechnol.

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Cutaneous chronic wounds are a major global health burden in continuous growth, because of population aging and the higher incidence of chronic diseases, such as diabetes. Different treatments have been proposed: biological, surgical, and physical. However, most of these treatments are palliative and none of them can be considered fully satisfactory. During a spontaneous wound healing, endogenous regeneration mechanisms and resident cell activity are triggered by the released platelet content. Activated stem and progenitor cells are key factors for ulcer healing, and they can be either recruited to the wound site from the tissue itself (resident cells) or from elsewhere. Transplant of skin substitutes, and of stem cells derived from tissues such as bone marrow or adipose tissue, together with platelet-rich plasma (PRP) treatments have been proposed as therapeutic options, and they represent the today most promising tools to promote ulcer healing in diabetes. Although stem cells can directly participate to skin repair, they primarily contribute to the tissue remodeling by releasing biomolecules and microvesicles able to stimulate the endogenous regeneration mechanisms. Stem cells and PRP can be obtained from patients as autologous preparations. However, in the diabetic condition, poor cell number, reduced cell activity or impaired PRP efficacy may limit their use. Administration of allogeneic preparations from healthy and/or younger donors is regarded with increasing interest to overcome such limitation. This review summarizes the results obtained when these innovative treatments were adopted in preclinical animal models of diabetes and in diabetic patients, with a focus on allogeneic preparations.

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“…The improvement in adhesion has been attributed to either an increased expression of other junctional adhesion proteins or a reduction in inflammatory mediators that impair DEJ adhesion. Optimizing the number and frequency of MSC infusions, while addressing specific MSC subpopulations like skin homing ATP-binding or cassette subfamily B member 5 positive (ABCB5) MSC (Riedl et al, 2021) are currently being studied and designed to improve the outcome results. Injection of MSC-derived anti-inflammatory products carried in exosomes (Perdoni et al, 2014;Shabbir et al, 2015;McBride et al, 2018) is similarly under investigation, as are HMGB1 and SDF1 able to attract MSC.…”

Section: Cell Therapymentioning

confidence: 99%

“…If this pathway is defective, this predisposes to cancer. Only very few therapeutic possibilities are available for these diseases ( de Andrade et al, 2021 ) ( Weon and Glass, 2019 ). Screening of a library comprising Food and Drug Administration (FDA)-approved drugs has shown that the sulfonylureas acetohexamide and glimepiride are able in vitro to enhance viability in XPA cells after UV radiation at rather high dosages ( Mazouzi et al, 2017 ).…”

Section: Interfering With the Pathophysiological Pathways Disturbed By The Mutated Genementioning

confidence: 99%

Challenges in Treating Genodermatoses: New Therapies at the Horizon

Morren

Legius

Giuliano³

et al. 2022

Front. Pharmacol.

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Genodermatoses are rare inherited skin diseases that frequently affect other organs. They often have marked effects on wellbeing and may cause early death. Progress in molecular genetics and translational research has unravelled many underlying pathological mechanisms, and in several disorders with high unmet need, has opened the way for the introduction of innovative treatments. One approach is to intervene where cell-signaling pathways are dysregulated, in the case of overactive pathways by the use of selective inhibitors, or when the activity of an essential factor is decreased by augmenting a molecular component to correct disequilibrium in the pathway. Where inflammatory reactions have been induced by a genetically altered protein, another possible approach is to suppress the inflammation directly. Depending on the nature of the genodermatosis, the implicated protein or even on the particular mutation, to correct the consequences or the genetic defect, may require a highly personalised stratagem. Repurposed drugs, can be used to bring about a “read through” strategy especially where the genetic defect induces premature termination codons. Sometimes the defective protein can be replaced by a normal functioning one. Cell therapies with allogeneic normal keratinocytes or fibroblasts may restore the integrity of diseased skin and allogeneic bone marrow or mesenchymal cells may additionally rescue other affected organs. Genetic engineering is expanding rapidly. The insertion of a normal functioning gene into cells of the recipient is since long explored. More recently, genome editing, allows reframing, insertion or deletion of exons or disruption of aberrantly functioning genes. There are now several examples where these stratagems are being explored in the (pre)clinical phase of therapeutic trial programmes. Another stratagem, designed to reduce the severity of a given disease involves the use of RNAi to attenuate expression of a harmful protein by decreasing abundance of the cognate transcript. Most of these strategies are short-lasting and will thus require intermittent life-long administration. In contrast, insertion of healthy copies of the relevant gene or editing the disease locus in the genome to correct harmful mutations in stem cells is more likely to induce a permanent cure. Here we discuss the potential advantages and drawbacks of applying these technologies in patients with these genetic conditions. Given the severity of many genodermatoses, prevention of transmission to future generations remains an important goal including offering reproductive choices, such as preimplantation genetic testing, which can allow selection of an unaffected embryo for transfer to the uterus.

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ABCB5+ Dermal Mesenchymal Stromal Cells with Favorable Skin Homing and Local Immunomodulation for Recessive Dystrophic Epidermolysis Bullosa Treatment

Cited by 23 publications

References 30 publications

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

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

Innovative Cell and Platelet Rich Plasma Therapies for Diabetic Foot Ulcer Treatment: The Allogeneic Approach

Challenges in Treating Genodermatoses: New Therapies at the Horizon

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