Jordan E Jackson1, Christopher Pivetti2, Sarah C Stokes3, Christina M Theodorou3, Priyadarsini Kumar2, Zachary J Paxton2, Alicia Hyllen2, Lizette Reynaga2, Aijun Wang2, Diana L Farmer3. 1. Division of Pediatric General, Thoracic and Fetal Surgery, University of California Davis Medical Center, Sacramento, California; Department of Surgery, University of California Davis, Sacramento, California. Electronic address: jorjack@ucdavis.edu. 2. Department of Surgery, University of California Davis, Sacramento, California. 3. Division of Pediatric General, Thoracic and Fetal Surgery, University of California Davis Medical Center, Sacramento, California; Department of Surgery, University of California Davis, Sacramento, California.
Abstract
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 × 105 cells/cm2. Immunodeficient mice were randomized to receive either an ECM only or PMSC-ECM administered into a subcutaneous pocket. Mice were monitored for tumor formation until two study endpoints: 4 wk and 6 mo. Pathology and histology on all tissues was performed to evaluate for tumors. Quantitative polymerase chain reaction (qPCR) was performed to evaluate for the presence of human DNA, which would indicate persistence of PMSCs. 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.
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 × 105 cells/cm2. Immunodeficient mice were randomized to receive either an ECM only or PMSC-ECM administered into a subcutaneous pocket. Mice were monitored for tumor formation until two study endpoints: 4 wk and 6 mo. Pathology and histology on all tissues was performed to evaluate for tumors. Quantitative polymerase chain reaction (qPCR) was performed to evaluate for the presence of human DNA, which would indicate persistence of PMSCs. 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.
Authors: Erin G Brown; Payam Saadai; Christopher D Pivetti; Michael S Beattie; Jacqueline C Bresnahan; Aijun Wang; Diana L Farmer Journal: J Pediatr Surg Date: 2013-10-05 Impact factor: 2.545
Authors: Israel M Barbash; Pierre Chouraqui; Jack Baron; Micha S Feinberg; Sharon Etzion; Ariel Tessone; Liron Miller; Esther Guetta; Dov Zipori; Laurence H Kedes; Robert A Kloner; Jonathan Leor Journal: Circulation Date: 2003-08-04 Impact factor: 29.690
Authors: Sarah C Stokes; Christina M Theodorou; Jordan E Jackson; Christopher Pivetti; Priyadarsini Kumar; Kaeli J Yamashiro; Zachary J Paxton; Lizette Reynaga; Alicia Hyllen; Aijun Wang; Diana L Farmer Journal: J Pediatr Surg Date: 2021-09-20 Impact factor: 2.549