Feasibility and safety of cellular therapy for in-utero repair of myelomeningocele (CuRe Trial): a first-in-human, phase 1, single-arm study.
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BACKGROUND: The Management of Myelomeningocele Study (MOMS) trial established the benefit of in-utero repair of myelomeningocele, with a decreased need for ventriculoperitoneal shunt placement. However, although there was some improvement of motor function, over half of the patients were unable to ambulate independently. Live placenta-derived mesenchymal stem cells (PMSCs) seeded on an extracellular matrix have shown promise in rescuing neurological function in the fetal ovine model of myelomeningocele. We aimed to evaluate the safety of this novel, living, stem cell product to augment the prenatal repair of myelomeningocele. METHODS: In this phase 1, first-in-human, single-dose, single-arm study, pregnant women who had fetuses diagnosed with myelomeningocele were enrolled in a staggered manner at University of California, Davis (UC Davis) School of Medicine, in Sacramento (CA, USA). Eligibility criteria were gestational age from 19 weeks to 26 weeks, upper boundary of the myelomeningocele defect between T1 and S1, hindbrain herniation shown by MRI, and normal karyotype. In-utero repair of the myelomeningocele was conducted with a single dose of topically applied allogeneic human PMSCs seeded on an extracellular matrix (Cook Biodesign Dural Graft [Cook Biotech; West Lafayette, IN, USA]). The PMSCs were generated from donated placentas collected from consented patients at the UC Davis Medical Center, and the cells were tested for identity, sterility, and viability 72 h before surgery. Primary safety endpoints included evaluation of the myelomeningocele repair site for healing, cerebrospinal fluid leak, infection, and unexpected abnormal growth or tumour formation. This study is registered with ClinicalTrials.gov (NCT04652908). FINDINGS: Between June 21, 2021, and Dec 5, 2022, six women with fetuses with gestational ages from 24+5 weeks to 25+5 weeks were enrolled in the study. Newborns were delivered at a median gestational age of 34+5 weeks (range 33+2 weeks to 36+6 weeks) by caesarean delivery. At birth, all infants had an intact repair site with no evidence of cerebrospinal fluid leak, infection, or abnormal tissue growth. After treatment, MRIs showed reversal of hindbrain herniation and no evidence of tumour formation. No cell-mediated adverse events occurred. INTERPRETATION: This first-in-human treatment consisting of allogeneic, live stem cells showed no cell-related adverse effects. The therapy was assessed as sufficiently safe to proceed with non-staggered enrolment of 35 patients in a phase 1/2a trial. FUNDING: California Institute for Regenerative Medicine and Shriners Children's.