Feasibility and safety of cellular therapy for in-utero repair of

# Feasibility and safety of cellular therapy for in-utero repair of myelomeningocele (CuRe Trial): a first-in-human, phase 1, single-arm study *The Lancet 2026* Articles Feasibility and safety of cellular therapy for in-utero repair of myelomeningocele (CuRe Trial): a first-in-human, phase 1, single-arm study Diana L Farmer, Priyadarsini Kumar, Elizabeth Reynolds, Su Yeon Lee, Amy B Powne, Christopher D Pivetti, Marike Zwienenberg, Amelia S McLennan, Jan A Nolta, Erin G Brown, Payam Saadai, Shinjiro Hirose, Aijun Wang Summary Background The Management of Myelomeningocele Study (MOMS) trial established the benefit of in-utero repair of Lancet 2026; 407: 867–75 myelomeningocele, with a decreased need for ventriculoperitoneal shunt placement. However, although there was See Comment page 827 some improvement of motor function, over half of the patients were unable to ambulate independently. Live placenta- Division of Pediatric General, derived mesenchymal stem cells (PMSCs) seeded on an extracellular matrix have shown promise in rescuing Thoracic, and Fetal Surgery, neurological function in the fetal ovine model of myelomeningocele. We aimed to evaluate the safety of this novel, Department of Surgery, University of California Davis living, stem cell product to augment the prenatal repair of myelomeningocele. Health, Sacramento, CA, USA (Prof D L Farmer MD, Methods In this phase 1, first-in-human, single-dose, single-arm study, pregnant women who had fetuses diagnosed E Reynolds MD, S Y Lee MD, with myelomeningocele were enrolled in a staggered manner at University of California, Davis (UC Davis) School of A B Powne MSN, E G Brown MD, P Saadai MD, Prof S Hirose MD); Medicine, in Sacramento (CA, USA). Eligibility criteria were gestational age from 19 weeks to 26 weeks, upper boundary Center for Bioengineering in of the myelomeningocele defect between T1 and S1, hindbrain herniation shown by MRI, and normal karyotype. In- Medicine, School of Medicine, utero repair of the myelomeningocele was conducted with a single dose of topically applied allogeneic human PMSCs University of California Davis seeded on an extracellular matrix (Cook Biodesign Dural Graft [Cook Biotech; West Lafayette, IN, USA]). The PMSCs Health, Sacramento, CA, USA (Prof D L Farmer, P Kumar PhD, were generated from donated placentas collected from consented patients at the UC Davis Medical Center, and the E Reynolds, S Y Lee, cells were tested for identity, sterility, and viability 72 h before surgery. Primary safety endpoints included evaluation of C D Pivetti MS, the myelomeningocele repair site for healing, cerebrospinal fluid leak, infection, and unexpected abnormal growth or Prof A Wang PhD); Institute for tumour formation. This study is registered with ClinicalTrials.gov (NCT04652908). Pediatric Regenerative Medicine, University of California Davis Health, c/o Findings Between June 21, 2021, and Dec 5, 2022, six women with fetuses with gestational ages from 24+⁵ weeks to 25+⁵ Shriners Children’s Northern weeks were enrolled in the study. Newborns were delivered at a median gestational age of 34+⁵ weeks (range 33+² weeks California, Sacramento, CA, USA (Prof D L Farmer, P Kumar, to 36+6 weeks) by caesarean delivery. At birth, all infants had an intact repair site with no evidence of cerebrospinal fluid Prof A Wang); Fetal Care and leak, infection, or abnormal tissue growth. After treatment, MRIs showed reversal of hindbrain herniation and no Treatment Center, University evidence of tumour formation. No cell-mediated adverse events occurred. of California Davis Health, Sacramento, CA, USA Interpretation This first-in-human treatment consisting of allogeneic, live stem cells showed no cell-related adverse (Prof D L Farmer, A B Powne, Prof M Zwienenberg MD, eects. The therapy was assessed as suciently safe to proceed with non-staggered enrolment of 35 patients in a A S McLennan MD, E G Brown, phase 1/2a trial. P Saadai, Prof S Hirose); Department of Neurological Funding California Institute for Regenerative Medicine and Shriners Children’s. Surgery, University of California Davis Health, Sacramento, CA, USA Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 (Prof M Zwienenberg); license. Department of Obstetrics and Gynecology, University of California Davis Health, Introduction these catastrophic conditions and require lifelong and Sacramento, CA, USA Neural tube defects, such as spina bifida, are a spectrum costly multidisciplinary care, leading to an enormous (A S McLennan); Stem Cell of congenital diseases with a substantial worldwide global disability burden. In 2014, spina bifida-related Program, Department of Internal Medicine, University burden, ranging in severity from minor disability to hospital charges were reported to be US$2 billion of California Davis Health, lethality. Globally, nearly half a million babies are born annually in the USA alone.6 The incidence of spina Sacramento, CA, USA every year with a neural tube defect.1,2 This figure is bifida in the USA is one in every 2800 births,7 with a (Prof J A Nolta PhD); likely to be an underestimation as there is variability in higher prevalence in people of Hispanic ethnicity than Department of Biomedical Engineering, University of reporting across dierent countries.3 Insight into in those of non-Hispanic White or non-Hispanic Black California Davis, Davis, CA, USA disease mechanism drove worldwide preventive eorts ethnicity.8 (Prof A Wang) in the form of vitamin fortification in foods,4 with the Myelomeningocele is the most severe form of spina discovery that folate supplementation in pregnancy bifida, whereby failure of neural tube closure early in fetal reduced the risk of neural tube defects resulting in the development results in leakage of cerebrospinal fluid and introduction of an important public health protective progressive damage to the fetal spinal cord from chemical measure.5 However, children are still born daily with and mechanical trauma caused by the amniotic fluid and Articles Correspondence to: Research in context Prof Diana L Farmer, Division of Pediatric General, Thoracic, and Evidence before this study preclinical work to identify the best stem cell source, rigorous Fetal Surgery, Department of Surgery, University of California Myelomeningocele is the most severe type of spina bifida, a translational research being required given the unknown effects Davis Health, Sacramento, neural tube defect leading to substantial disability across the of allogeneic stem cells on the fetal CNS. CA 95817, USA lifespan, including paralysis and bowel, bladder, and kidney dlfarmer@health.ucdavis.edu Added value of this study failure. The Management for Myelomeningocele Study or This study shows the safety of placenta-derived mesenchymal established that fetal surgery to repair the neural tube defect Dr Aijun Wang, Center for stem cells (PMSCs) to treat a CNS disorder before birth. To our improved outcomes by reducing the need for shunting Bioengineering in Medicine, knowledge, this trial is the first phase 1 study in humans to Department of Surgery, procedures for hydrocephalus. Although most prenatally investigate the safety and feasibility of a tissue-engineering University of California Davis operated children were still unable to walk, motor function of approach to treat myelomeningocele in utero. Allogeneic Health, Sacramento, CA 95817, the legs was improved. This observation gave us hope that we USA PMSCs seeded on an extracellular matrix graft applied topically could further advance neurological outcomes for these children aawang@health.ucdavis.edu to the exposed spinal cord at the time of in-utero repair of using stem cells. Many studies have explored different surgical myelomeningocele had no unexpected adverse outcomes techniques, but there are no published human clinical trials related to the stem cell product. Specifically, there were no evaluating the safety or efficacy of stem cells of any kind to difficulties with wound healing or any instances of abnormal treat spina bifida in utero, nor are there any commercially tissue growth or tumour formation. available stem cell products to treat fetuses for any condition. We have conducted numerous searches across several Implications of all the available evidence databases including PubMed, Embase, and Scopus, with no Stem cell therapy at the time of standard prenatal surgery for date limitations or language restrictions (most recently on myelomeningocele does not interfere with the known benefits Aug 1, 2025). Searches were comprised of terms such as of fetal surgery and is not associated with any cell-related “myelomeningocele”, “spina bifida”, “surgery”, “in utero”, adverse effects. Phase 1/2a is ongoing to evaluate the long- “fetal”, “prenatal”, “stem cell”, and “stem cell transplantation”. term safety and preliminary efficacy of the product. Therefore, this trial began with more than a decade of uterine wall, respectively.9 This damage results in myelomeningocele, the exposed fetal spinal cord has a numerous abnormalities in development, including distorted architecture and an increased number of Arnold-Chiari II malformation with hindbrain herniation, apoptotic cells.12 A murine model of myelomeningocele hydrocephalus, and other brain abnormalities, as well as evaluated with scanning electron microscopy showed loss of motor function below the level of the spinal cord typical development of the spinal cord in the initial stages lesion, leading to paralysis and bowel and bladder of myelomeningocele, with tissue damage progressing dysfunction. These outcomes are explained by a two-hit throughout gestation.13 Together, these studies suggest hypothesis—the first hit arising from abnormalities in that the root cause of disability is spinal cord injury in the anatomical development of the spinal cord and the utero. Therefore, a reparative, regenerative, anti-apoptotic second from damage to the cord caused by chemical and treatment could augment the in-utero surgical closure, mechanical trauma in utero. repair the spinal cord damage, and prevent the catastrophic Myelomeningocele remains the only nervous system symptoms associated with myelomeningocele. This vision defect that is routinely repaired in utero and the only catalysed over a decade of preclinical work focused on non-lethal disease for which fetal surgery is oered. developing a feasible and safe therapeutic approach that Historically, myelomeningocele was treated with would complement—and not compromise—the known postnatal closure of the defect to prevent infection. benefits of in-utero repair of myelomeningocele. The However, in 2011, the Management of Myelomeningocele translational pathway leading to Investigational New Drug Study (MOMS)10 showed that in-utero repair of the (IND) approval is outlined in figure 1. myelomeningocele defect was safe, leading to decreased The neurorestorative eects of mesenchymal stem cells hindbrain herniation, reduced need for cerebrospinal are well documented and include promotion of neurite fluid shunting, and improved distal neurological outgrowth, secretion of anti-apoptotic and neuroprotective function. Nonetheless, 58% of the prenatally operated factors, and regulation of inflammation.20 Multiple cell children were unable to independently ambulate at types were investigated as therapeutic candidates, 30 months.11 A considerable gap remains between the including induced pluripotent stem cell-derived neural outcomes of the current standard of care and the goal of crest stem cells15 and placenta-derived mesenchymal stem independent ambulation for all patients. cells (PMSCs). In-utero repair of myelomeningocele might protect The placenta is a unique, extra-embryonic tissue that against progressive spinal cord injury, but it does not has a fundamental role in orchestrating fetal development reverse damage that has already occurred. An autopsy throughout gestation, regulating nutrient transfer, and study showed that in human patients with modulating immunological tolerance.29,30 Initially, the 868 Articles Human induced pluripotent stem cell- Manufacture and preparation of human Long-term safety derived neural crest stem cells integrate into placenta-derived mesenchymal stromal cells evaluation of placental the injured spinal cord in the fetal lamb for local tissue delivery. mesenchymal stromal model of myelomeningocele. Lankford et al (2017)20 cells for in utero repair Saadai et al (2013)15 Placental mesenchymal stromal cells seeded of myelomeningocele in on clinical grade extracellular matrix improve a novel ovine model. ambulation in ovine myelomeningocele. Stokes et al (2022)27 Kabagambe et al (2018)21 Efficacy of clinical-grade human placental High density placental mesenchymal mesenchymal stromal stromal cells provide neuronal preservation cells in fetal ovine and improve motor function following in myelomeningocele utero treatment of ovine myelomeningocele. repair. Vanover et al (2019)22 Theodorou et al (2022)28 MOMS First patient treated published (CuRe Trial) Exploration and preparation Preclinical and translational studies IND-enabling studies Phase 1 clinical trial 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Prenatal repair of myelomeningocele with Innate healing in the fetal sheep model of Placental mesenchymal stromal cells: aligned nanofibrous scaffolds—a pilot study myelomeningocele: a standardized defect preclinical safety evaluation for fetal in sheep. grading system. myelomeningocele repair. Saadai et al (2011)14 Brown et al (2015)16 Jackson et al (2021)24 Development of a locomotor rating scale for Surviving lambs with myelomeningocele testing motor function in sheep. repaired in utero with placental Brown et al (2015)17 mesenchymal stromal cells for 6 months: a Age does matter: a pilot comparison of pilot study. placenta-derived stromal cells for in utero Yamashiro et al (2020)25 repair of myelomeningocele using a lamb In utero treatment of myelomeningocele model. with placental mesenchymal stromal cells— Brown et al (2016)18 selection of an optimal cell line in Placental mesenchymal stromal cells rescue preparation for clinical trials. ambulation in ovine myelomeningocele. Galganski et al (2020)26 Wang et al (2015)19 Neuroprotective effect of placenta-derived mesenchymal stromal cells: role of exosomes. Kumar et al (2019)23 Figure 1: Translational pathway and preclinical development timeline leading to the first-in-human in-utero stem cell therapy for spina bifida The schematic shows the preclinical work that led to IND approval, encompassing evaluation of different stem cell sources, including neural crest cells;14,15 discovery of the benefits of placental tissue-derived stem cells; standardisation of an animal model for rigorous assessment of therapies;16,17 assessment of the efficacy and neuroprotective mechanisms of PMSCs;20,23 development of the PMSC-ECM product;21 selection and manufacturing of clinical grade cell lines; and, finally, establishment of the safety and efficacy of the clinical-grade product in a fetal lamb model.24–26,28 Timeline reflects online publication dates. CuRe=Cellular Therapy for In Utero Repair of Myelomeningocele. IND=Investigational New Drug. MOMS=Management of Myelomeningocele Study. PMSC=placenta-derived mesenchymal stem cells. PMSC-ECM=placenta-derived mesenchymal stem cells-extracellular matrix. placenta was an attractive candidate as a source of reported in the literature, including biocellulose patches,34 autologous cells as the cells can be obtained readily the product used in this study is distinct in that its through the well-established technique of chorionic villus primary purpose is to serve as a cellular delivery vehicle, sampling.31 We discovered that PMSCs obtained in early with the added benefit of already being approved by the gestation were an ideal therapeutic candidate due to their US Food and Drugs Administration (FDA). fetal origin, absent tumerogenicity, neuroprotective eect, Notably, PMSCs have rescued ambulation in an ovine and anti-apoptotic capability. When cultured in a specific model of spina bifida.22 Overall, previous studies neurogenic medium, they can be uniquely culture adapted suggested that allogeneic stem cells were a reasonable to secrete higher concentrations of neurogenic growth choice to test in human fetuses and potentially preferable factors and can rescue apoptotic neurons in vitro.19,23 to further exploring autologous sources, with the added PMSCs also have immunomodulatory properties and benefit of sparing pregnant individuals the known potential for ex vivo expansion.32,33 Compared with adult procedural risks of chorionic villus sampling (which bone marrow-derived mesenchymal stem cells, PMSCs include a small chance of pregnancy loss).31 However, secrete higher quantities of key neurotrophic growth until now, the safety of allogeneic PMSCs for fetal factors, including brain-derived neurotrophic factor and applications was unknown. hepatocyte growth factor.33 The engagement of cell surface In preclinical dose-escalating ovine studies and IND- receptors with matrix molecules when PMSCs are enabling studies (IND 24097) using the most eective cell cultured on an extracellular matrix scaold could further density, in-utero surgical repair of myelomeningocele with enhance the survival and biological functions of these PMSCs seeded on an FDA-approved extracellular matrix cells. Although several dural substitutes have been (PMSC-ECM, using Cook Biodesign Dural Graft) resulted Articles in substantial improvements in motor function compared relevant standard operating procedures in the UC Davis with extracellular matrix alone22 and restored normal Good Manufacturing Practice facility. bowel and bladder function.28,35 Here, we report the 72 h before the scheduled fetal myelomeningocele feasibility and safety results of Cellular Therapy for In repair, PMSCs were thawed and tested for identity, Utero Repair of Myelomeningocele (CuRe Trial)—a sterility, and viability. The PMSC-ECM product was phase 1, first-in-human study of PMSC-ECM with live cells formulated by seeding PMSCs onto Cook Biodesign topically applied over the exposed spinal cord during Dural Graft (Cook Biotech; West Lafayette, IN, USA) at a in-utero repair of myelomeningocele. density of 300 000 cells/cm² and incubating for 24 h at 37°C in 5% CO. Before use, the product underwent Methods additional sterility testing. Study design We conducted a phase 1, investigator-initiated, first-in- Surgical procedure human, single-centre, single-dose study designed to Patients underwent general anaesthesia with epidural evaluate the safety of the PMSC-ECM topically applied to placement, and a low transverse laparotomy was used to the exposed spinal cord of eligible fetuses with expose the uterus. The operative technique used in this myelomeningocele during fetal surgery. The protocol trial follows the procedure described in MOMS,10 which was approved by the University of California, Davis (UC provides the only validated data and serves as our Davis) Institutional Review Board (approval number historical control group. The only addition was the 1617774). Written informed consent was obtained from placement of the PMSC-ECM product. Briefly, a 5–8 cm participants before the start of the study. The study was hysterotomy was made after confirming placental overseen by the FDA (IND 24097), the California Institute location with ultrasonography. The fetus was positioned for Regenerative Medicine (CIRM), and an independent to expose the myelomeningocele defect through the data safety monitoring board (DSMB). The study was hysterotomy. The PMSC-ECM product was delivered conducted through close cooperation between the study sterilely to the operating room. After neurosurgical funder and the FDA. This study is registered with dissection of the neural placode, the PMSC-ECM was ClinicalTrials.gov (NCT04652908). topically applied directly onto the neural placode, with the cells in contact with the exposed fetal spinal cord, Study participants followed by primary closure of the dura or duraplasty Inclusion and exclusion criteria followed those used in using the PMSC-ECM product, and closure of the fetal See Online for appendix MOMS10 (appendix). In summary, patients between skin, hysterotomy, and maternal abdomen. An overview gestational ages 19 weeks and 26 weeks with a of the CuRe trial procedure and timeline is depicted in myelomeningocele defect (including myeloschisis) from the appendix. After the surgery, weekly targeted T1 to S1, hindbrain herniation shown by MRI, and normal ultrasonography was done until delivery to monitor the karyotype were eligible. Non-singleton pregnancy, fetal repair site and overall wellbeing of the fetus. anomaly unrelated to myelomeningocele, maternal contraindications to surgery, conditions for increased risk Primary outcomes of preterm birth, and psychosocial limitations were major The primary endpoints were the safety and feasibility of reasons for exclusion. the PMSC-ECM product. Feasibility was defined as the ability to administer the investigational treatment— Preparation of PMSCs ie, apply the product at the time of surgery—for all Human PMSC cell lines were generated from donated patients. Safety was defined as the absence of the placentas collected from consented patients at the UC following, assessed during birth hospitalisation: postnatal Davis Medical Center (CA, USA). Chorionic villus tissue cerebrospinal fluid leak, evaluated by physical examination was dissected from placentas, and PMSCs were expanded and spinal ultrasonography at birth; clinical evidence of and cryopreserved following the IND protocol and all infection at the fetal myelomeningocele repair site, evaluated by physical examination assessing for erythema or other visual signs of infection; failure of the Expected event Number to trigger rate DSMB review myelomeningocele repair site to heal, evaluated by physical examination to assess for wound dehiscence; Maternal death 0 1 tumour formation, evaluated by contrast-enhanced MRI, Perinatal death 0·03 1 assessing for abnormal tissue growth at the repair site; Cerebrospinal fluid leak 0·011 2 and any patient deaths. The myelomeningocele repair site Dehiscence of 0·13 3 myelomeningocele repair was documented by photography within 24 h of birth and assessed at birth by physical examination by the treating DSMB=data safety monitoring board. neonatologist, paediatric neurosurgeons, fetal surgeons, Table 1: Expected rate of adverse events and numbers of events at which and research team. MRI was done within 2 weeks of birth review by the DSMB would be triggered or as soon as the neonate was clinically stable. 870 Articles Maternal Gravida, para Lesion level* Hindbrain Myeloschisis Fetal lateral ventricle Clubfoot Gestational age (years) herniation vs myelomeningocele size on MRI age at surgery 1 35 Gravida 4, para 3 L2/3 Yes Myelomeningocele 7 mm (right), No 25+ weeks 12·5 mm (left) 2 23 Gravida 2, para 0 L1 Yes Myelomeningocele 11 mm bilaterally No 25+ weeks 3 28 Gravida 2, para 1 L4 Yes Myelomeningocele 11 mm bilaterally Yes 25+ weeks 4 25 Gravida 1, para 0 S1 Yes Myelomeningocele 13 mm bilaterally No 25+ weeks 5 36 Gravida 5, para 4 S1 Yes Myeloschisis 15 mm (right), No 24+ weeks 18 mm (left) 6 27 Gravida 5, para 2 L3 Yes Myelomeningocele 12 mm bilaterally Yes 25+ weeks *As ascertained by the cranial aspect of the lesion on prenatal ultrasonography. Table 2: Characteristics of patients at the time of surgery A B C Figure 2: Intraoperative steps of in-utero myelomeningocele repair using PMSC-ECM (A) Maternal laparotomy and hysterotomy are done to expose the fetal myelomeningocele lesion. (B) The spinal cord is dissected from the surrounding tissue, and the PMSC-ECM product is tailored to the size of the defect and applied topically, directly on the exposed spinal cord, cell side facing down (indicated by circle). (C) The fetal skin is closed over the dura. PMSC-ECM=placenta-derived mesenchymal stem cells-extracellular matrix. Treatment of patients was staggered, as maximum PPROM Gestational Birthweight (g) Hindbrain PMSC-ECM Cerebrospinal Length of stay caution was required, given the unknown outcomes of age at birth herniation related fluid diversion until discharge putting living stem cells into the fetal CNS. No (weeks) adverse procedure for home (days) subsequent patient was enrolled until the previous child events hydrocephalus prior to was delivered and assessed for cell-related complications, discharge as mandated by FDA-approved protocol. Data collection 1 No 36+ 3565 No None No 5 and enrolment was halted when the sixth patient reached 2 Yes 35+ 2575 No None No 9 the age of 3 months for data analysis and determination 3 No 36+ 2730 No None No 8 of sucient safety of the PMSC-ECM to warrant continuation of the trial. 4 Yes 33+ 2320 No None No 28 5 Yes 34+ 2065 No None No 17 Statistical analysis 6 Yes 33+ 2075 No None No 30 Data are outlined in a descriptive manner according to PPROM=preterm premature rupture of membranes. PMSC-ECM=placenta-derived mesenchymal stem cells- the prespecified primary endpoints of this phase 1 extracellular matrix. study. Our protocol and statistical plan mandated that Table 3: Characteristics of patients at birth accrual would be halted for DSMB review if the frequency of a specific adverse event exceeded the threshold that would be expected to occur with less than 5% probability, given an expected event rate based Role of the funding source on the MOMS study.10 Event rates required to trigger The funders of the study had no role in study design, DSMB review are shown in table 1. It should be noted data collection, data analysis, data interpretation, or that although the risk of perinatal death in the MOMS writing of the report. Annual reports to CIRM are trial was 3%,10 we chose to have a single perinatal death submitted as a condition for ongoing milestone-based trigger a DSMB review as any perinatal death must be funding. CIRM continues to serve in an advisory capacity, investigated to ensure it is not due to the experimental assist with enrolment, and identify any concerns related treatment. to patients or trial conduct. Articles Results preventing PMSC-ECM product from being applied or Between June 21, 2021, and Dec 5, 2022, six pregnant the fetal repair from being accomplished (figure 2). patients assigned female sex at birth and of median age There were no intra-operative complications requiring 27·5 years (range 23–36 years) were enrolled in the trial. maternal or fetal transfusions, maternal or fetal All six patients were White (non-Hispanic). All had fetuses resuscitation, or emergent delivery of the fetus. with myelomeningocele (except for one with myeloschisis) Newborns were delivered at a median gestational age diagnosed on second trimester ultrasonography, with the of 34+⁵ weeks (range 33+² weeks to 36+⁶ weeks) by lesion level ranging from L1 to S1 and presence of caesarean delivery (table 3). Two infant patients were hindbrain herniation confirmed on fetal MRI (table 2). born before 34 weeks of gestation, with one infant Gestational age at surgery ranged from 24+⁵ weeks to requiring intubation because of transient respiratory 25+⁵ weeks. There were no technical complications distress syndrome related to prematurity. All infants were discharged without a requirement for home oxygen. CuRe (first MOMS (prenatal All baseline characteristics were similar to those reported six patients) repair group)10 in the MOMS trial (table 4). Maternal age, years 23–36 29·3 (5·3) All newborns were found to have an intact repair site, Lesion level* with no evidence of cerebrospinal fluid leak, infection, Thoracic 0 4 (5%) skin separation, or abnormal tissue (tumour) growth on physical examination (figure 3). Postnatal MRI L1–L2 2 (33%) 21 (27%) obtained as soon as the newborns were clinically stable L3–L4 2 (33%) 30 (38) showed reversal of hindbrain herniation (figure 4, L5–S1 2 (33%) 23 (29%) tables 2, 3). No evidence of abnormal tissue Gestational age at surgery, weeks 24+ to 25+ 23·6 (1·4)† proliferation or tumour formation was seen on Gestational age at birth, weeks 33+ to 36+ 34·1 (3·1) postnatal imaging. No infant patients required a shunt Data are range, mean (SD), or n (%). CuRe=Cellular Therapy for In Utero Repair to treat hydrocephalus before being discharged. The of Myelomeningocele. MOMS=Management of Myelomeningocele Study. *As ascertained by the cranial aspect of the lesion on prenatal ultrasonography. median corrected gestational age at discharge was 37+⁴ †Gestational age at random assignment. weeks (range 36+⁴ weeks to 37+⁵ weeks). Of note, all patient data and images are presented in a randomised Table 4: Baseline maternal and fetal characteristics in CuRe and MOMS order. Figure 3: Postnatal evaluation of the surgical repair site following in-utero myelomeningocele repair Each patient’s repaired defect was evaluated at birth. Macroscopic images of the surgery site confirmed that all the patients had an intact repair site, with no evidence of cerebrospinal fluid leak or infection. Figure 4: Prenatal and postnatal MRI showing reversal of hindbrain herniation following in-utero myelomeningocele repair with PMSC-ECM Hindbrain herniation was confirmed by MRI in all six patients before repair (top row). Following repair of the myelomeningocele defect with the PMSC-ECM product, postnatal MRI within 2 weeks of birth showed reversal of hindbrain herniation (bottom row). Arrowheads in each image indicate the location of the hindbrain. PMSC-ECM=placenta-derived mesenchymal stem cells-extracellular matrix. 872 latanerP latantsoP Articles Discussion the small initial sample size of six patients and the focus This trial constitutes the translation of a rationally limited to birth outcomes in this report. Long-term designed, mechanistically informed regenerative therapy follow-up of all enrolled patients (up to age 6 years) will into clinical application, leveraging PMSCs specifically provide a more definitive assessment of both safety and engineered to modulate the intrauterine environment at preliminary ecacy. the site of the exposed spinal cord in myelomeningocele. Currently, no regenerative stem cell products are The PMSCs were designed to attenuate neuro- commercially available to treat diseases in utero. The inflammation, reduce neuronal apoptosis, and secrete fetal environment contains numerous qualities that neurotrophic and growth factors that support neural could facilitate stem cell therapy, including the natural tissue preservation and spinal cord integrity. These receptivity of the developing fetus to regeneration and therapeutic mechanisms were previously validated remodelling by stem cells.40 Recently, two studies have through in-vitro neuroprotection assays23 and both small evaluated the safety and ecacy of in-utero stem cell and large animal models.19,21,25,27,36 PMSCs are intended to transplantation for the severe genetic disorders protect and regenerate the injured fetal spinal cord thalassaemia (a bleeding disorder) and osteogenesis during a crucial window of fetal neurodevelopment, imperfecta (a collagen disorder).41,42 In-utero intravenous complementing the mechanical benefits of surgical transplantation of maternal bone marrow-derived repair with a biologically active strategy aimed at hematopoietic stem cells for thalassaemia and of improving long-term neurological outcomes. allogeneic fetal liver-derived stem cell for osteogenesis There was appropriate pretrial concern about the imperfecta appeared safe, but long-term engraftment for unknown eects of placing allogeneic PMSCs into the genetic conditions is challenging and continues to be fetal CNS. Therefore, this phase 1 trial focused on the optimised. In contrast, long-term engraftment is not surgical feasibility and early safety of combining PMSC warranted for myelomeningocele, which is a structural therapy with standard fetal myelomeningocele repair in a birth defect with a defined anatomical area requiring carefully monitored clinical cohort. The outcomes transient regeneration and repair. PMSCs have shown showed the safe application of PMSC-ECM, without immunomodulatory, neuroprotective, and wound- interference with the known saltatory eects of fetal healing properties in vitro and ecacy in vivo in animal surgery or evidence of adverse events related to stem cell models of fetal myelomeningocele repair.19,22,28 Until now, application in the fetal CNS during pregnancy. the use of PMSCs in human fetal patients, particularly Specifically, all patients had reversal of hindbrain with these cells in direct contact with the delicate and herniation. No patients had evidence of abnormal tissue developing CNS, had not been studied. growth or tumour formation on physical exam or In patients with myelomeningocele, prenatal repair has postnatal imaging. At birth, the repair site appeared been shown to reduce hindbrain herniation and rates of indistinguishable from those of patients who underwent ventriculoperitoneal shunt.10 However, prenatal surgery prenatal repair without the stem cell product in the does not fully address the mobility issues that arise from MOMS trial.10 Evaluating these safety endpoints was damage to lower motor neurons. The initial findings of crucial to confirm that the anti-inflammatory properties this study indicated that PMSC-ECM directly applied to of the stem cell product did not impair fetal wound the fetal spinal cord during prenatal repair of healing, particularly as previous studies in the ovine myelomeningocele was without cell-related adverse events model showed that the anti-inflammatory characteristics and that hindbrain herniation was reversed. The safety of the amnion contributed to failed healing.37 All results of the first six patients have been deemed to be six patients had complete healing of their fetal wound at adequate by the DSMB and FDA to allow continuation of birth and, as of Aug 1, 2025, no patients have had any the trial with more aggressive, non-staggered enrolment. wound complications attributable to the stem cell Although some motor function observations can be product. made after birth, their clinical validity remains uncertain; The potential for tumour development in fetal patients therefore, these findings are not included in this phase 1 receiving stem cell therapy is of concern in two potential safety study report. In addition to routine care, follow-up scenarios: malignant or proliferative transformation of assessments will be done at 3 months, 6 months, the transplanted PMSCs and exuberant growth of the 9 months, 12 months, 18 months, 24 months, and cells of the fetus through the eects of PMSCs. To date, 30 months and then annually, until age 6 years. Long-term there are no reported cases in the literature of abnormal outcomes include long-term safety; motor function, tested tissue or tumour growth after the use of mesenchymal using validated tools (Test of Infant Motor Performance,43 stromal or stem cells in adult patients.38,39 Our study is Alberta Infant Motor Scale,44 Bayley Scale of Infant the first to show the feasibility and safety of PMSC-ECM Development,45 Peabody Developmental Motor Scales,46 for use in prenatal therapy for a CNS disorder, directly the WeeFIM test,47 and the Ages & Stages Questionnaires); applied to the anatomical site of pathology. Although bowel and bladder function (assessed with anorectal these phase 1 endpoints showed adequate safety to manometry and urodynamics); and results of any imaging proceed to the phase 2a stage of the trial, we acknowledge or procedures. The ongoing phase 1/2a study will continue Articles the assessment of the long-term safety and preliminary 5 Czeizel AE, Dudás I. Prevention of the first occurrence of neural- ecacy of the PMSC-ECM for improving motor function, tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327: 1832–35. as well as bowel and bladder function. 6 Inouye BM, Jiang R, Alkazemi MH, et al. Hospital and ED charges This trial establishes a scalable and clinically feasible for spina bifida care in the United States between 2006 and 2014: platform for the targeted delivery of biological therapeutics over $2 billion annually. Disabil Health J 2019; 12: 431–36. to the fetus. The successful integration of cell-based 7 Stallings EB, Isenburg JL, Rutkowski RE, et al. National population- based estimates for major birth defects, 2016–2020. Birth Defects Res therapy into fetal surgery, under stringent regulatory 2024; 116: e2301. oversight and within a standardised surgical workflow, 8 Canfield MA, Mai CT, Wang Y, et al, and the National Birth Defects shows the feasibility and safety of delivering rationally Prevention Network. The association between race/ethnicity and major birth defects in the United States, 1999–2007. designed biologics during gestation. By intervening at Am J Public Health 2014; 104: e14–23. early stages of development, this approach has the 9 Copp AJ, Adzick NS, Chitty LS, Fletcher JM, Holmbeck GN, potential to alter lifelong health trajectories, reducing the Shaw GM. Spina bifida. Nat Rev Dis Primers 2015; 1: 15007. 10 Adzick NS, Thom EA, Spong CY, et al, and the MOMS burden of chronic disability and minimising the Investigators. A randomized trial of prenatal versus postnatal repair long-term social and economic impact of these conditions. of myelomeningocele. N Engl J Med 2011; 364: 993–1004. 11 Farmer DL, Thom EA, Brock JW, 3rd, et al. The Management of Contributors Myelomeningocele Study: full cohort 30-month pediatric outcomes. The following authors were responsible for aspects of study design Am J Obstet Gynecol 2018; 218: 256.e1–13. pertinent to their expertise—medical and regulatory oversight: DLF, 12 Wang L, Lin S, Yi D, et al. Apoptosis, expression of PAX3 and P53, ABP, SYL, MZ, JAN, ASM, SH, PS, and EGB; product formulation and and caspase signal in fetuses with neural tube defects. delivery: PK and AW; enrolment of study participants: DLF, ABP, SYL; Birth Defects Res 2017; 109: 1596–604. and collection of data and analysis of findings: DLF, SYL, CDP, AW, and 13 Stiefel D, Meuli M. Scanning electron microscopy of fetal murine ER. All authors were engaged in manuscript preparation and confirm myelomeningocele reveals growth and development of the spinal adherence to protocol, the completeness and accuracy of results, and the cord in early gestation and neural tissue destruction around birth. collective decision to publish the paper. DLF, AW, ER, SYL, CDP, and PK J Pediatr Surg 2007; 42: 1561–65. directly accessed and verified the data. 14 Saadai P, Nout YS, Encinas J, et al. Prenatal repair of myelomeningocele with aligned nanofibrous scaolds—a pilot Declaration of interests study in sheep. J Pediatr Surg 2011; 46: 2279–83. DLF and AW report the following disclosures: US patent 15 Saadai P, Wang A, Nout YS, et al. Human induced pluripotent stem number 10058572 (issued Aug 28, 2018) from US patent cell-derived neural crest stem cells integrate into the injured spinal application 14/912066 (filed Aug 14, 2014); US patent number 11583557 cord in the fetal lamb model of myelomeningocele. J Pediatr Surg (issued Feb 21, 2023) from US patent application 15/998529 (filed 2013; 48: 158–63. Aug 16, 2018); and US patent application 18/098631 (filed 18, 2023). 16 Brown EG, Keller BA, Pivetti CD, Farmer DL. Innate healing in the All patents are assigned to the Regents of the University of California, fetal sheep model of myelomeningocele: a standardized defect Davis. All other authors declare no competing interests. grading system. J Pediatr Surg 2015; 50: 1134–36. Data sharing 17 Brown EG, Keller BA, Pivetti CD, et al. Development of a locomotor Study-related documents including study protocol, statistical analysis rating scale for testing motor function in sheep. J Pediatr Surg 2015; plan, informed consent form, and de-identified participant data can be 50: 617–21. made available on request at the conclusion of this trial and on 18 Brown EG, Keller BA, Lankford L, Pivetti CD, Hirose S, publication of related manuscripts. Farmer DL, Wang A. Age does matter: a pilot comparison of placenta-derived stromal cells for in utero repair of Acknowledgments myelomeningocele using a lamb model. Fetal Diagn Ther 2016; This trial has been supported by research grants from the California 39: 179–85. Institute for Regenerative Medicine ([CIRM] PC1-08103, CLIN1-11404, 19 Wang A, Brown EG, Lankford L, et al. Placental mesenchymal and CLIN2-12129) and Shriners Children’s (72008-NCA-21 and 70012- stromal cells rescue ambulation in ovine myelomeningocele. NCA-23). We would like to acknowledge clinical research coordinator Stem Cells Transl Med 2015; 4: 659–69. Maria Navarro and the following individuals who helped generate the 20 Lankford L, Chen YJ, Saenz Z, et al. Manufacture and preparation clinical grade PMSC-ECM product used in the phase 1 portion of the of human placenta-derived mesenchymal stromal cells for local clinical trial: Lizette Reynaga, Alicia Hyllen, Mounika Bhaskara, tissue delivery. Cytotherapy 2017; 19: 680–88. Samantha Avallone, Brandon Light, and Meiby Ramos. We also wish to 21 Kabagambe S, Keller B, Becker J, et al. Placental mesenchymal acknowledge the sta members of UC Davis Alpha Stem Cell Clinic, stromal cells seeded on clinical grade extracellular matrix improve GMP facility, and Quality Control Testing Laboratory for their ambulation in ovine myelomeningocele. J Pediatr Surg 2018; assistance in this study; Natalie Tobin for administrative assistance, 53: 178–82. William Gruenloh for regulatory support, Sandra Taylor for 22 Vanover M, Pivetti C, Lankford L, et al. High density placental biostatistics consultation, and the University of California Davis mesenchymal stromal cells provide neuronal preservation and Clinical and Translational Science Center for trial management improve motor function following in utero treatment of ovine support. myelomeningocele. J Pediatr Surg 2019; 54: 75–79. 23 Kumar P, Becker JC, Gao K, et al. Neuroprotective eect of References placenta-derived mesenchymal stromal cells: role of exosomes. 1 Kancherla V. Neural tube defects: a review of global prevalence, FASEB J 2019; 33: 5836–49. causes, and primary prevention. Childs Nerv Syst 2023; 39: 1703–10. 24 Jackson JE, Pivetti C, Stokes SC, et al. Placental mesenchymal 2 Kancherla V, Botto LD, Rowe LA, et al. Preventing birth defects, stromal cells: preclinical safety evaluation for fetal saving lives, and promoting health equity: an urgent call to action myelomeningocele repair. J Surg Res 2021; 267: 660–68. for universal mandatory food fortification with folic acid. 25 Yamashiro K, Galganski LA, Peyton J, et al. Surviving lambs with Lancet Glob Health 2022; 10: e1053–57. myelomeningocele repaired in utero with placental mesenchymal 3 Yacob A, Carr CJ, Foote J, et al. The global burden of neural tube stromal cells for 6 months: a pilot study. Fetal Diagn Ther 2020; defects and disparities in neurosurgical care. World Neurosurg 2021; 47: 912–17. 149: e803–20. 26 Galganski LA, Kumar P, Vanover MA, et al. In utero treatment of 4 Atta CA, Fiest KM, Frolkis AD, et al. Global birth prevalence of myelomeningocele with placental mesenchymal stromal cells— spina bifida by folic acid fortification status: a systematic review and selection of an optimal cell line in preparation for clinical trials. meta-analysis. 2016; 106: e24–34. J Pediatr Surg 2020; 55: 1941–46. 874 Articles 27 Stokes SC, Theodorou CM, Jackson JE, et al. Long-term safety 38 Casiraghi F, Remuzzi G, Abbate M, Perico N. Multipotent evaluation of placental mesenchymal stromal cells for in utero mesenchymal stromal cell therapy and risk of malignancies. repair of myelomeningocele in a novel ovine model. J Pediatr Surg Stem Cell Rev Rep 2013; 9: 65–79. 2022; 57: 18–25. 39 Musiał-Wysocka A, Kot M, Majka M. The pros and cons of 28 Theodorou CM, Stokes SC, Jackson JE, et al. Ecacy of clinical- mesenchymal stem cell-based therapies. Cell Transplant 2019; grade human placental mesenchymal stromal cells in fetal ovine 28: 801–12. myelomeningocele repair. J Pediatr Surg 2022; 57: 753–58. 40 Hu MS, Rennert RC, McArdle A, et al. The role of stem cells during 29 Cindrova-Davies T, Sferruzzi-Perri AN. Human placental scarless skin wound healing. Adv Wound Care 2014; 3: 304–14. development and function. Semin Cell Dev Biol 2022; 131: 66–77. 41 Sagaru RL, Åström E, Chitty LS, et al. An exploratory open-label 30 Jansson T. Placenta plays a critical role in maternal-fetal resource multicentre phase I/II trial evaluating the safety and ecacy of allocation. Proc Natl Acad Sci USA 2016; 113: 11066–68. postnatal or prenatal and postnatal administration of allogeneic 31 Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic expanded fetal mesenchymal stem cells for the treatment of severe villus sampling for prenatal diagnosis. Cochrane Database Syst Rev osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial 2003; 3: CD003252. protocol. BMJ Open 2024; 14: e079767. 32 Moonshi SS, Adelnia H, Wu Y, Ta HT. Placenta-derived 42 MacKenzie TC, Frascoli M, Sper R, et al. In utero stem cell mesenchymal stem cells for treatment of diseases: a clinically transplantation in patients with alpha thalassemia major: interim relevant source. Adv Ther 2022; 5: 2200054. results of a phase 1 clinical trial. Blood 2020; 136 (suppl 1): 1. 33 Poloni A, Rosini V, Mondini E, et al. Characterization and 43 Campbell S. The Test of Infant Motor Performance, test user’s expansion of mesenchymal progenitor cells from first-trimester manual version 3.0. Performance Motor Scales, 2012. chorionic villi of human placenta. Cytotherapy 2008; 10: 690–97. 44 Piper MC, Pinnell LE, Darrah J, Maguire T, Byrne PJ. Construction 34 Lapa DA, Acácio GL, Trigo L, et al. Biocellulose patch technique for and validation of the Alberta Infant Motor Scale (AIMS). fetoscopic repair of open spina bifida in twin pregnancy. Can J Public Health 1992; 83 (suppl 2): S46–50. Ultrasound Obstet Gynecol 2023; 62: 558–64. 45 Balasundaram P, Avulakunta ID. Bayley Scales of Infant and 35 Theodorou CM, Jackson JE, Stokes SC, et al. Early investigations Toddler Development. StatPearls, 2025. into improving bowel and bladder function in fetal ovine 46 Folio MFR. Peabody Developmental Motor Scales—second edition myelomeningocele repair. J Pediatr Surg 2022; 57: 941–48. (PDMS-2): examiner’s manual. Pro-Ed, 2000. 36 Chen YJ, Chung K, Pivetti C, et al. Fetal surgical repair with 47 Uniform Data System. The WeeFIM II clinical guide version 6.0. placenta-derived mesenchymal stromal cell engineered patch in Uniform Data System for Medical Rehabilitation, 2006. a rodent model of myelomeningocele. J Pediatr Surg 2018; 53: 183–88. 37 Brown EG, Saadai P, Pivetti CD, et al. In utero repair of myelomeningocele with autologous amniotic membrane in the fetal lamb model. J Pediatr Surg 2014; 49: 133–37, discussion 137–38. --- [PDF原文](https://sci-net.xyz/storage/7932541/ff6c848614085fe92b6dd36355b49567f9d0a9aa47e687a95cfe3ce765b130d1/Feasibility-and-safety-of-cellular-therapy-for-in-utero-repair-of-myelomeningocele-CuRe-Trial.pdf) DOI: 10.1016/S0140-6736(25)02466-3