Myelomeningocele (MMC), the most severe form of spina bifida (SB), is a birth defect that occurs due to the incomplete closure of the neural tube during early pregnancy. The spinal cord is thus exposed to chemical damage from the amniotic fluid and mechanical damage from the uterine wall for the remainder of the pregnancy term, incurring additional damage. This congenital injury results in lifelong paralysis. The current standard of care treatment for MMC is fetal surgical closure of the defect. However, the fetal surgery treatment results in only 44.8% of treated children who are able to walk independently at 30 months of age. Our group aims to reverse the MMC associated paralysis and improve motor function outcomes in MMC children by augmenting the current standard of care surgery with a stem cell regenerative product. Placenta-derived mesenchymal stromal cells (PMSCs), isolated from human donors, have neuroprotective abilities that have been shown to improve motor function in our gold-standard fetal sheep model of MMC. We have developed a PMSC product under current Good Manufacturing Practices (cGMP), as required by the FDA, by seeding human clinical-grade PMSCs on a dural extracellular matrix (ECM), generating the PMSC-ECM stem cell product we aimed to evaluate for safety in this study.
The PMSC-ECM product was evaluated for safety in an immunocompromised mouse model, NID/SCID/Gamma-/- (NSG). Two experimental groups were evaluated, a total of 54 mice. One group of NSG mice (26 mice) received the PMSC-ECM patch subcutaneously (placed under the skin), and the other group of NSG mice (28 mice) received just an ECM patch subcutaneously. Both groups of mice were monitored for tumor formation at 4 weeks and 6 months post-implantation of the patches. We hypothesized that the clinical-grade PMSC-ECM product would not cause any tumor formation in the immunocompromised mice at 4 weeks or at 6 months. We also hypothesized that there would be no presence of human DNA to indicate the persistence of human PMSCs in the mouse system.
Pathology and histology were performed to evaluate for tumors, and results showed no evidence of any tumor development. Quantitative polymerase chain reaction (qPCR) was done to look for human DNA, which would indicate the presence of human PMSCs. Results showed no evidence of human DNA to indicate the persistence of human PMSCs at either study end points of 4 weeks or 6 months. These results support our hypothesis and the overall safety of the PMSC-ECM product to proceed to be evaluated in a Phase 1/2a human clinical trial.