Allogeneic ABCB5+ Mesenchymal Stem Cells for Treatment-Refractory Chronic Venous Ulcers: A Phase I/IIa Clinical Trial

Kerstan, Andreas; Dieter, Kathrin; Niebergall-Roth, Elke; Dachtler, Ann-Kathrin; Kraft, Korinna; Stücker, Markus; Daeschlein, Georg; Jünger, Michael; Görge, Tobias; Meyer-Pannwitt, Ulrich; Erfurt‐Berge, Cornelia; Engelhardt, Charlotte von; Klare, Andreas; Pfeiffer, Christiane; Esterlechner, Jasmina; Schröder, Hannes M.; Gasser, Martin; Waaga-Gasser, Ana Maria; Goebeler, Matthias; Ballikaya, Seda; Sadeghi, Samar; Murphy, Gëorge F.; Orgill, Dennis P.; Frank, Natasha Y.; Ganss, Christoph; Scharffetter‐­Kochanek, Karin; Frank, Markus H.; Kluth, Mark A.

doi:10.1016/j.xjidi.2021.100067

Cited by 21 publications

(21 citation statements)

References 56 publications

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“…A recent trial evaluating intravenously injected ABCB5+ allogeneic skinderived hMSCs in patients with epidermolysis bullosa reported two patients with severe, yet transient and manageable, hypersensitivity reactions (11). We, however, even after repeated topical application (three subsequent doses), found no or only mild signs of an adverse immune response in our preclinical model, similar to previous studies (10,64,65). Ardanaz et al conclude that once no hypersensitivity response to a second pooled allogeneic BM-MSC injection is observed, repeated treatments are possible to potentiate the benefit of hMSC therapy (66).…”

Section: Discussionsupporting

confidence: 89%

“…Specifically, MSCs can improve wound healing, most likely by secreting factors associated with chemoattraction, cell proliferation and differentiation, immunomodulation, angiogenesis, antiapoptosis, anti-fibrosis, and even anti-microbial effects (1,(5)(6)(7). This has led to several promising preclinical studies, as well as phase I and II clinical trials targeting chronic skin wounds, venous ulcers and epidermolysis bullosa (8)(9)(10)(11). Yet, transition to phase III and IV clinical trials, or even marketing authorization, is remarkably slow.…”

Section: Introductionmentioning

confidence: 99%

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Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

et al. 2022

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Human Mesenchymal Stromal Cells (hMSCs) are a promising source for cell-based therapies. Yet, transition to phase III and IV clinical trials is remarkably slow. To mitigate donor variabilities and to obtain robust and valid clinical data, we aimed first to develop a manufacturing concept balancing large-scale production of pooled hMSCs in a minimal expansion period, and second to test them for key manufacture and efficacy indicators in the clinically highly relevant indication wound healing. Our novel clinical-scale manufacturing concept is comprised of six single donor hMSCs master cell banks that are pooled to a working cell bank from which an extrapolated number of 70,000 clinical doses of 1x106 hMSCs/cm2 wound size can be manufactured within only three passages. The pooled hMSC batches showed high stability of key manufacture indicators such as morphology, immune phenotype, proliferation, scratch wound healing, chemotactic migration and angiogenic support. Repeated topical hMSCs administration significantly accelerated the wound healing in a diabetic rat model by delivering a defined growth factor cargo (specifically BDNF, EGF, G-CSF, HGF, IL-1α, IL-6, LIF, osteopontin, VEGF-A, FGF-2, TGF-β, PGE-2 and IDO after priming) at the specific stages of wound repair, namely inflammation, proliferation and remodeling. Specifically, the hMSCs mediated epidermal and dermal maturation and collagen formation, improved vascularization, and promoted cell infiltration. Kinetic analyses revealed transient presence of hMSCs until day (d)4, and the dynamic recruitment of macrophages infiltrating from the wound edges (d3) and basis (d9), eventually progressing to the apical wound on d11. In the wounds, the hMSCs mediated M2-like macrophage polarization starting at d4, peaking at d9 and then decreasing to d11. Our study establishes a standardized, scalable and pooled hMSC therapeutic, delivering a defined cargo of trophic factors, which is efficacious in diabetic wound healing by improving vascularization and dynamic recruitment of M2-like macrophages. This decision-making study now enables the validation of pooled hMSCs as treatment for impaired wound healing in large randomized clinical trials.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

et al. 2022

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“…Recently, a skin-resident immunomodulatory MSC population ( 38 – 40 ), marked by the ATP-Binding Cassette Transporter, Subfamily B, Member 5 (ABCB5; ABCB5 + dermal MSCs, ABCB5 + MSCs; ref. 41 ), has been shown to promote healing of chronic wounds after therapeutic administration in preclinical and clinical studies ( 40 , 42 , 43 ). The observed effects could be attributed to IL‑1RA released by the MSCs, which shifted the prevalence of proinflammatory M1 macrophages toward antiinflammatory, repair-promoting M2 macrophages in the wound tissue ( 40 ).…”

Section: Introductionmentioning

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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“…In a chronic wound model mimicking human chronic venous ulcers, ABCB5 + MSCs shifted the M1 macrophage prevalence toward an M2 phenotype via secretion of IL-1 receptor antagonist (IL-1RA) and rescued impaired angiogenesis in the wound bed [53]. These effects were associated with an acceleration of wound healing, which was also observed in human chronic venous ulcers treated with ABCB5 + MSCs [54,55]. Very recently, angiogenesis-and healing-promoting efficacy of ABCB5 + MSCs was demonstrated also in a mouse diabetic wound model [50].…”

Section: Introductionmentioning

confidence: 85%

Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers

et al. 2022

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Background While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. Methods The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. Results Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. Conclusions The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. Trial registration: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784

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Allogeneic ABCB5+ Mesenchymal Stem Cells for Treatment-Refractory Chronic Venous Ulcers: A Phase I/IIa Clinical Trial

Cited by 21 publications

References 56 publications

Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

Pooled human bone marrow-derived mesenchymal stromal cells with defined trophic factors cargo promote dermal wound healing in diabetic rats by improved vascularization and dynamic recruitment of M2-like macrophages

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

Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers

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