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

Dimitra Kiritsi; Kathrin Dieter; Elke Niebergall-Roth; Silvia Fluhr; Cristina Daniele; Jasmina Esterlechner; Samar Sadeghi; Seda Ballikaya; Leoni Erdinger; Franziska Schauer; Stella Gewert; Martin Laimer; Johann W. Bauer; Alain Hovnanian; Giovanna Zambruno; May El Hachem; Emmanuelle Bourrat; Maria Papanikolaou; Gabriela Petrof; Sophie Kitzmüller; Christen L. Ebens; Markus H. Frank; Natasha Y. Frank; Christoph Ganss; Anna E. Martinez; John A. McGrath; Jakub Tolar; Mark A. Kluth

doi:10.1172/jci.insight.151922

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

Dimitra Kiritsi, Kathrin Dieter, Elke Niebergall-Roth, Silvia Fluhr, Cristina Daniele, Jasmina Esterlechner, Samar Sadeghi, Seda Ballikaya, Leoni Erdinger, Franziska Schauer, Stella Gewert, Martin Laimer, Johann W. Bauer, Alain Hovnanian, Giovanna Zambruno, May El Hachem, Emmanuelle Bourrat, Maria Papanikolaou, Gabriela Petrof, Sophie KitzmüllerChristen L. Ebens, Markus H. Frank, Natasha Y. Frank, Christoph Ganss, Anna E. Martinez, John A. McGrath, Jakub Tolar, Mark A. Kluth^*

^*Corresponding author for this work

Dermatology

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and lifethreatening 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. METHODS. In 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 × 10⁶ABCB5+ 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 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. CONCLUSION. This 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.

Original language	English
Article number	e151922
Journal	JCI Insight
Volume	6
Issue number	22
Early online date	19 Oct 2021
DOIs	https://doi.org/10.1172/jci.insight.151922
Publication status	Published - 22 Nov 2021

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Kiritsi, D., Dieter, K., Niebergall-Roth, E., Fluhr, S., Daniele, C., Esterlechner, J., Sadeghi, S., Ballikaya, S., Erdinger, L., Schauer, F., Gewert, S., Laimer, M., Bauer, J. W., Hovnanian, A., Zambruno, G., El Hachem, M., Bourrat, E., Papanikolaou, M., Petrof, G., ... Kluth, M. A. (2021). Clinical trial of ABCB5⁺mesenchymal stem cells for recessive dystrophic epidermolysis bullosa. JCI Insight, 6(22), Article e151922. https://doi.org/10.1172/jci.insight.151922

@article{7b23b682e9384cbdab987e530068c63a,

title = "Clinical trial of ABCB5+mesenchymal stem cells for recessive dystrophic epidermolysis bullosa",

abstract = "BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and lifethreatening 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. METHODS. In 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 × 106ABCB5+ 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 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. CONCLUSION. This 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.",

author = "Dimitra Kiritsi and Kathrin Dieter and Elke Niebergall-Roth and Silvia Fluhr and Cristina Daniele and Jasmina Esterlechner and Samar Sadeghi and Seda Ballikaya and Leoni Erdinger and Franziska Schauer and Stella Gewert and Martin Laimer and Bauer, {Johann W.} and Alain Hovnanian and Giovanna Zambruno and {El Hachem}, May and Emmanuelle Bourrat and Maria Papanikolaou and Gabriela Petrof and Sophie Kitzm{\"u}ller and Ebens, {Christen L.} and Frank, {Markus H.} and Frank, {Natasha Y.} and Christoph Ganss and Martinez, {Anna E.} and McGrath, {John A.} and Jakub Tolar and Kluth, {Mark A.}",

note = "Funding Information: FUNDING. The 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. Publisher Copyright: {\textcopyright} 2021 American Society for Clinical Investigation. All rights reserved.",

year = "2021",

month = nov,

day = "22",

doi = "10.1172/jci.insight.151922",

language = "English",

volume = "6",

journal = "JCI Insight",

issn = "2379-3708",

publisher = "The American Society for Clinical Investigation",

number = "22",

}

Kiritsi, D, Dieter, K, Niebergall-Roth, E, Fluhr, S, Daniele, C, Esterlechner, J, Sadeghi, S, Ballikaya, S, Erdinger, L, Schauer, F, Gewert, S, Laimer, M, Bauer, JW, Hovnanian, A, Zambruno, G, El Hachem, M, Bourrat, E, Papanikolaou, M, Petrof, G, Kitzmüller, S, Ebens, CL, Frank, MH, Frank, NY, Ganss, C, Martinez, AE, McGrath, JA, Tolar, J & Kluth, MA 2021, 'Clinical trial of ABCB5⁺mesenchymal stem cells for recessive dystrophic epidermolysis bullosa', JCI Insight, vol. 6, no. 22, e151922. https://doi.org/10.1172/jci.insight.151922

TY - JOUR

T1 - Clinical trial of ABCB5+mesenchymal stem cells for recessive dystrophic epidermolysis bullosa

AU - Kiritsi, Dimitra

AU - Dieter, Kathrin

AU - Niebergall-Roth, Elke

AU - Fluhr, Silvia

AU - Daniele, Cristina

AU - Esterlechner, Jasmina

AU - Sadeghi, Samar

AU - Ballikaya, Seda

AU - Erdinger, Leoni

AU - Schauer, Franziska

AU - Gewert, Stella

AU - Laimer, Martin

AU - Bauer, Johann W.

AU - Hovnanian, Alain

AU - Zambruno, Giovanna

AU - El Hachem, May

AU - Bourrat, Emmanuelle

AU - Papanikolaou, Maria

AU - Petrof, Gabriela

AU - Kitzmüller, Sophie

AU - Ebens, Christen L.

AU - Frank, Markus H.

AU - Frank, Natasha Y.

AU - Ganss, Christoph

AU - Martinez, Anna E.

AU - McGrath, John A.

AU - Tolar, Jakub

AU - Kluth, Mark A.

N1 - Funding Information: FUNDING. The 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. Publisher Copyright: © 2021 American Society for Clinical Investigation. All rights reserved.

PY - 2021/11/22

Y1 - 2021/11/22

N2 - BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and lifethreatening 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. METHODS. In 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 × 106ABCB5+ 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 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. CONCLUSION. This 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.

AB - BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and lifethreatening 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. METHODS. In 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 × 106ABCB5+ 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 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. CONCLUSION. This 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.

UR - http://www.scopus.com/inward/record.url?scp=85120356995&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.151922

DO - 10.1172/jci.insight.151922

M3 - Article

C2 - 34665781

AN - SCOPUS:85120356995

SN - 2379-3708

VL - 6

JO - JCI Insight

JF - JCI Insight

IS - 22

M1 - e151922

ER -

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

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