Human skin-derived ABCB5+ stem cell injection improves liver disease parameters in Mdr2KO mice

Hartwig, Vanessa; Dewidar, Bedair; Lin, Tao; Dropmann, A; Ganss, Christoph; Kluth, Mark A.; Tappenbeck, Nils; Tietze, Lysann; Christ, Bruno; Frank, Markus H.; Vogelmann, Roger; Ebert, Matthias; Dooley, Steven

doi:10.1007/s00204-019-02533-3

Cited by 10 publications

(11 citation statements)

References 72 publications

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“…The substantial anti-inflammatory potential of ABCB5 + MSCs and their convincing safety profile make our ATMP a promising candidate for intravenous treatment of systemic inflammatory conditions as well. Thus far, significant benefit delivered by human ABCB5 + MSCs in pre-clinical models of epidermolysis bullosa [ 53 ] and liver disease [ 54 ] has stimulated further clinical trials of allogeneic ABCB5 + MSCs in recessive dystrophic epidermolysis bullosa ( NCT03529877 ) and acute-on-chronic liver failure ( NCT03860155 ).…”

Section: Discussionmentioning

confidence: 99%

Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data

Kerstan

Niebergall-Roth²,

Esterlechner³

et al. 2021

Cytotherapy

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Background aim: Mesenchymal stromal cells (MSCs) hold promise for the treatment of tissue damage and injury. However, MSCs comprise multiple subpopulations with diverse properties, which could explain inconsistent therapeutic outcomes seen among therapeutic attempts. Recently, the adenosine triphosphate-binding cassette transporter ABCB5 has been shown to identify a novel dermal immunomodulatory MSC subpopulation. Methods: The authors have established a validated Good Manufacturing Practice (GMP)-compliant expansion and manufacturing process by which ABCB5 + MSCs can be isolated from skin tissue and processed to generate a highly functional homogeneous cell population manufactured as an advanced therapy medicinal product (ATMP). This product has been approved by the German competent regulatory authority to be tested in a clinical trial to treat therapy-resistant chronic venous ulcers. Results: As of now, 12 wounds in nine patients have been treated with 5 £ 10 5 autologous ABCB5 + MSCs per cm 2 wound area, eliciting a median wound size reduction of 63% (range, 32À100%) at 12 weeks and early relief of pain. Conclusions: The authors describe here their GMP-and European Pharmacopoeia-compliant production and quality control process, report on a pre-clinical dose selection study and present the first in-human results. Together, these data substantiate the idea that ABCB5 + MSCs manufactured as ATMPs could deliver a clinically relevant wound closure strategy for patients with chronic therapy-resistant wounds.

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Section: Discussionmentioning

confidence: 99%

Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data

Kerstan

Niebergall-Roth²,

Esterlechner³

et al. 2021

Cytotherapy

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“…In contrast, in situations of excessive, detrimental ECM deposition, ABCB5 + MSCs have appeared to be capable of reducing the amount of deposited collagen. In the Mdr2 −/− mouse model of established cholestatic liver fibrosis, intravenously injected ABCB5 + MSCs significantly reduced collagen deposition, particularly in the periportal region [125]. The observed reduction was not associated with changes in liver tissue expression of αSMA and smooth muscle protein 22α, marker proteins of activated hepatic stellate cells and portal fibroblasts, which are the major contributors to cholestatic liver fibrosis [126,127].…”

Section: Ecm Remodelingmentioning

confidence: 93%

Skin-Derived ABCB5+ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine

Niebergall-Roth¹,

Frank

Ganss

et al. 2022

IJMS

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The ATP-binding cassette superfamily member ABCB5 identifies a subset of skin-resident mesenchymal stem cells (MSCs) that exhibit potent immunomodulatory and wound healing-promoting capacities along with superior homing ability. The ABCB5+ MSCs can be easily accessed from discarded skin samples, expanded, and delivered as a highly homogenous medicinal product with standardized potency. A range of preclinical studies has suggested therapeutic efficacy of ABCB5+ MSCs in a variety of currently uncurable skin and non-skin inflammatory diseases, which has been substantiated thus far by distinct clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. Therefore, skin-derived ABCB5+ MSCs have the potential to provide a breakthrough at the forefront of MSC-based therapies striving to fulfill current unmet medical needs. The most recent milestones in this regard are the approval of a phase III pivotal trial of ABCB5+ MSCs for treatment of recessive dystrophic and junctional epidermolysis bullosa by the US Food and Drug Administration, and national market access of ABCB5+ MSCs (AMESANAR®) for therapy-refractory chronic venous ulcers under the national hospital exemption pathway in Germany.

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“…Covering all three principal mechanisms (i.e., immunomodulation, adaptive secretion of anti-inflammatory and pro-angiogenic biomolecules, and multilineage differentiation) by which MSCs can contribute to inflammation control and tissue repair, skin-derived ABCB5 + MSCs offer a broad spectrum of potential therapeutic indications associated not only with skinrelated but also systemic inflammatory and/or degenerative processes. In preclinical studies, ABCB5 + MSCs delivered significant benefit in mouse models of chronic skin wounds [6], epidermolysis bullosa [10], and liver disease [11]. In a first in-human clinical trial, topically applied ex vivo-expanded ABCB5 + MSCs facilitated wound closure of standard therapyresistant chronic venous ulcers [7].…”

Section: Introductionmentioning

confidence: 99%

Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: off-the-shelf GMP-manufactured donor-independent ATMP

Ballikaya¹,

Sadeghi²,

Niebergall-Roth³

et al. 2020

Stem Cell Res Ther

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Background Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an easily accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated not only with skin-related but also systemic inflammatory and/or degenerative processes. Methods We have developed a validated Good Manufacturing Practice-compliant expansion and manufacturing process by which ABCB5+ MSCs derived from surgical discard skin tissues are processed to an advanced-therapy medicinal product (ATMP) for clinical use. Enrichment for ABCB5+ MSCs is achieved in a three-step process involving plastic adherence selection, expansion in a highly efficient MSC-selecting medium, and immunomagnetic isolation of the ABCB5+ cells from the mixed culture. Results Product Quality Review data covering 324 cell expansions, 728 ABCB5+ MSC isolations, 66 ABCB5+ MSC batches, and 85 final drug products reveal high process robustness and reproducible, reliable quality of the manufactured cell therapy product. Conclusion We have successfully established an expansion and manufacturing process that enables the generation of homogenous ABCB5+ MSC populations of proven biological activity manufactured as a standardized, donor-independent, highly pure, and highly functional off-the-shelf available ATMP, which is currently tested in multiple clinical trials.

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Human skin-derived ABCB5+ stem cell injection improves liver disease parameters in Mdr2KO mice

Cited by 10 publications

References 72 publications

Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data

Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data

Skin-Derived ABCB5+ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine

Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: off-the-shelf GMP-manufactured donor-independent ATMP

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