Placental Mesenchymal Stromal Cells: Preclinical Safety Evaluation for Fetal Myelomeningocele Repair.
Cellular retention
Myelomeningocele
Safety
Stromal cells
Tumorigenicity
Journal
The Journal of surgical research
ISSN: 1095-8673
Titre abrégé: J Surg Res
Pays: United States
ID NLM: 0376340
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
04
12
2020
revised:
01
06
2021
accepted:
09
06
2021
pubmed:
18
7
2021
medline:
7
4
2022
entrez:
17
7
2021
Statut:
ppublish
Résumé
Myelomeningocele (MMC) is the congenital failure of neural tube closure in utero, for which the standard of care is prenatal surgical repair. We developed clinical-grade placental mesenchymal stromal cells seeded on a dural extracellular matrix (PMSC-ECM), which have been shown to improve motor outcomes in preclinical ovine models. To evaluate the long-term safety of this product prior to use in a clinical trial, we conducted safety testing in a murine model. Clinical grade PMSCs obtained from donor human placentas were seeded onto a 6 mm diameter ECM at a density of 3 × 10 Fifty-four mice were included; 13 received ECM only and 14 received PMSC-ECM in both the 4-wk and 6-mo groups. No mice had gross or microscopic evidence of tumor development. A nodular focus of mature fibrous connective tissue was identified at the subcutaneous implantation pocket in the majority of mice with no significant difference between ECM only and PMSC-ECM groups (P = 0.32 at 4 wk, P > 0.99 at 6 mo). Additionally, no human DNA was detected by qPCR in any mice at either time point. Subcutaneous implantation of the PMSC-ECM product did not result in tumor formation and we found no evidence that PMSCs persisted. These results support the safety of the PMSC-ECM product for use in a Phase 1/2a human clinical trial evaluating fetal MMC repair augmented with PMSC-ECM.
Sections du résumé
BACKGROUND
Myelomeningocele (MMC) is the congenital failure of neural tube closure in utero, for which the standard of care is prenatal surgical repair. We developed clinical-grade placental mesenchymal stromal cells seeded on a dural extracellular matrix (PMSC-ECM), which have been shown to improve motor outcomes in preclinical ovine models. To evaluate the long-term safety of this product prior to use in a clinical trial, we conducted safety testing in a murine model.
METHODS
Clinical grade PMSCs obtained from donor human placentas were seeded onto a 6 mm diameter ECM at a density of 3 × 10
RESULTS
Fifty-four mice were included; 13 received ECM only and 14 received PMSC-ECM in both the 4-wk and 6-mo groups. No mice had gross or microscopic evidence of tumor development. A nodular focus of mature fibrous connective tissue was identified at the subcutaneous implantation pocket in the majority of mice with no significant difference between ECM only and PMSC-ECM groups (P = 0.32 at 4 wk, P > 0.99 at 6 mo). Additionally, no human DNA was detected by qPCR in any mice at either time point.
CONCLUSIONS
Subcutaneous implantation of the PMSC-ECM product did not result in tumor formation and we found no evidence that PMSCs persisted. These results support the safety of the PMSC-ECM product for use in a Phase 1/2a human clinical trial evaluating fetal MMC repair augmented with PMSC-ECM.
Identifiants
pubmed: 34273796
pii: S0022-4804(21)00379-6
doi: 10.1016/j.jss.2021.06.011
pmc: PMC9365330
mid: NIHMS1825460
pii:
doi:
Types de publication
Journal Article
Randomized Controlled Trial, Veterinary
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
660-668Subventions
Organisme : NINDS NIH HHS
ID : R01 NS100761
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS115860
Pays : United States
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
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