Hematopoietic Stem Cell Transplantation with Mesenchymal Stromal Cells in Children with Metachromatic Leukodystrophy

Karin Melanie Cabanillas Stanchi; Judith Böhringer; Manuel Strölin; Samuel Groeschel; Katrin Lenglinger; Claudia Treuner; Christiane Kehrer; Lucia Laugwitz; Andrea Bevot; Nadja Kaiser; Michael Schumm; Peter Lang; Rupert Handgretinger; Ingeborg Krägeloh-Mann; Ingo Müller; Michaela Döring

doi:10.1089/scd.2021.0352

Hematopoietic Stem Cell Transplantation with Mesenchymal Stromal Cells in Children with Metachromatic Leukodystrophy

Stem Cells Dev. 2022 Apr;31(7-8):163-175. doi: 10.1089/scd.2021.0352.

Authors

Karin Melanie Cabanillas Stanchi¹, Judith Böhringer², Manuel Strölin², Samuel Groeschel², Katrin Lenglinger¹, Claudia Treuner¹, Christiane Kehrer², Lucia Laugwitz², Andrea Bevot², Nadja Kaiser², Michael Schumm¹, Peter Lang¹, Rupert Handgretinger¹, Ingeborg Krägeloh-Mann², Ingo Müller³, Michaela Döring¹

Affiliations

¹ General Pediatrics, Hematology and Oncology, University Children's Hospital Tübingen, Tübingen, Germany.
² Neuropediatrics, University Children's Hospital Tübingen, Tübingen, Germany.
³ Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

PMID: 35323019
DOI: 10.1089/scd.2021.0352

Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder primarily affecting the white matter of the nervous system that results from a deficiency of the arylsulfatase A (ARSA). Mesenchymal stem cells (MSCs) are able to secrete ARSA and have shown beneficial effects in MLD patients. In this retrospective analysis, 10 pediatric MLD patients [mesenchymal stem cell group (MSCG)] underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received two applications of 2 × 10⁶ MSCs/kg bodyweight at day +30 and +60 after HSCT between 2007 and 2018. MSC safety, occurrence of graft-versus-host disease (GvHD), blood ARSA levels, chimerism, cell regeneration and engraftment, magnetic resonance imaging (MRI) changes, and the gross motor function were assessed within the first year of HSCT. The long-term data included clinical outcomes and safety aspects of MSCs. Data were compared to a control cohort of seven pediatric MLD patients [control group (CG)] who underwent HSCT only. The application of MSC in pediatric MLD patients after allogeneic HSCT was safe and well tolerated, and long-term potentially MSC-related adverse effects up to 13.5 years after HSCT were not observed. Patients achieved significantly higher ARSA levels (CG: median 1.03 nmol·10^-6 and range 0.41-1.73 | MSCG: median 1.58 nmol·10^-6 and range 0.44-2.6; P < 0.05), as well as significantly higher leukocyte (P < 0.05) and thrombocyte (P < 0.001) levels within 365 days of MSC application compared to CG patients. Statistically significant effects on acute GvHD, regeneration of immune cells, MRI changes, gross motor function, and clinical outcomes were not detected. In conclusion, the application of MSCs in pediatric MLD patients after allogeneic HSCT was safe and well tolerated. The two applications of 2 × 10⁶/kg allogeneic MSCs were followed by improved engraftment and hematopoiesis within the first year after HSCT. Larger, prospective trials are necessary to evaluate the impact of MSC application on engraftment and hematopoietic recovery.

Keywords: GMFCS-MLD; aryl-sulfatase A; hematopoietic stem cell transplantation; mesenchymal stem cells; mesenchymal stromal cells; metachromatic leukodystrophy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Child
Graft vs Host Disease* / etiology
Hematopoietic Stem Cell Transplantation* / methods
Humans
Leukodystrophy, Metachromatic* / etiology
Leukodystrophy, Metachromatic* / therapy
Mesenchymal Stem Cell Transplantation* / adverse effects
Mesenchymal Stem Cells* / physiology
Prospective Studies
Retrospective Studies