Cellular Therapy for In Utero Repair of Myelomeningocele - The CuRe Trial

Official title

Phase 1/2a Trial of Placental Mesenchymal Stem Cells for Repair of Fetal Myelomeningocele

Overview

Spina bifida, or myelomeningocele (MMC), is a birth defect that results in paralysis, excess fluid on the brain (hydrocephalus), and impaired ability to urinate and have bowel movements normally. In a previous study (the MOMS trial), surgery before birth (in-utero/fetal surgery) was shown to reduce the need for shunting for hydrocephalus. There was also some improvement in ambulation, but 58 % of the children still could not walk unassisted. This study is testing living stem cells from placenta added to the fetal repair in an effort to improve the ability to walk. Previous animal studies have shown dramatic improvement in walking and bowel and bladder function when placental stem cells are added to MMC repair. Use of these "living" cells may protect the developing spinal cord, prevent further injury, and may even reverse existing damage to the nerves that control movement. This study is assessing the safety and efficacy of adding stem cells to open fetal surgery for MMC in humans.

Detailed description

Historically, treatment of MMC was limited to post-natal surgery to close the dura and skin over the spinal cord to prevent meningitis, which had no effect on motor function. The potential benefit of earlier intervention was realized when prenatal ultrasound of patients with MMC early in gestation revealed near-normal leg movements despite displaying paralysis at birth. This finding gave credence to the two-hit hypothesis that paralysis was progressive during prenatal life and suggested that fetal intervention could prevent the secondary damage to the spinal cord. Fetal repair of MMC did confer improvement in motor function of children treated in the Management of Myelomeningocele (MOMS) randomized controlled trial. The promising results of the MOMS trial demonstrated the potential for improvement of paralysis for these patients, but distal motor function still remained severely impaired in the majority of patients with MMC with standard in utero repair alone. While this demonstrated that the ideal time to intervene to prevent paralysis is in utero with the goal of preventing the accrual of ongoing damage to the spinal cord, there is still room for improvement. The remarkable regenerative capacity of the fetal environment combined with regenerative capacity of placental mesenchymal stem cells offers potential for augmentation of the fetal repair of MMC with a novel therapy to further reduce and repair the sustained spinal cord damage.

Interventions

• Biological Placental Mesenchymal Stem Cells seeded on a commercially available dural graft extracellular matrix
  As in the current standard fetal surgery, under sonographic guidance, initial uterine entry will be accomplished by uterine stapling device or similar. The fetus will be given an intramuscular injection of pain medications and paralytic. The myelomeningocele will be closed in a standardized manner under magnification. As in the standard fetal operation, the spinal cord will be dissected from surrounding tissue and allowed to drop into the spinal canal. The PMSC-ECM product will then be tailored
• Other Untreated contemporaneous cohort
  The addition of a non-PMSC treated cohort, the untreated contemporaneous cohort, has been added at the request of the FDA to provide contemporaneous patients for validation of the continued relevance of use of the outcomes of the MOMS trial as the comparison arm for the Phase 2a portion of the study.

Primary outcome measures

• Safety of the placenta-derived mesenchymal stem cell (PMSC-ECM) Product [Time frame: Assessed at birth]

Secondary outcome measures (1)

• Efficacy of the PMSC-ECM Product [Time frame: 30 months.]

Eligibility criteria

Inclusion criteria

Eligibility for fetal surgery per the MOMS trial, which are:

• Myelomeningocele (including myeloschisis) at any level from T1 through S1 with hindbrain herniation. Lesion level will be confirmed by ultrasound and hindbrain herniation will be confirmed by MRI at the UC Davis Fetal Center
• Maternal age ≥18 years
• Gestational age at enrollment between 19 weeks 0 days and 25 weeks 6 days gestation as determined by clinical information and evaluation of first ultrasound
• Normal karyotype. Results by fluorescence in situ hybridization (FISH) will be acceptable if the patient is greater than 24 weeks gestation;

Exclusion criteria

Not being eligible for fetal surgery per the MOMS trial, which includes:

• Multifetal pregnancy
• Insulin dependent pregestational diabetes
• Fetal anomaly not related to myelomeningocele.
• Kyphosis in the fetus of 30 degrees or more
• Current or planned cerclage or documented history of incompetent cervix, placenta previa or placental abruption
• Short cervix < 20 mm measured by cervical ultrasound
• Obesity as defined by body mass index of 35 or greater
• Previous spontaneous singleton delivery prior to 37 weeks
• Maternal-fetal Rh isoimmunization, Kell sensitization or a history of neonatal alloimmune thrombocytopenia
• Maternal HIV or Hepatitis-B status positive due to the increased risk of transmission to the fetus during maternal-fetal surgery. If the patient's HIV or Hepatitis B status is unknown, the patient must be tested and found to have negative results before she can be enrolled
• Known Hepatitis-C positivity. If the patient's Hepatitis C status is unknown, she does not need to be screened
• Uterine anomaly such as large or multiple fibroids or Müllerian duct abnormality
• Other maternal medical condition which is a contraindication to surgery or general anesthesia. This includes any patient with a previous hysterotomy in the active segment of the uterus (whether from a previous classical cesarean, uterine anomaly such as an arcuate or bicornuate uterus, major myomectomy resection, or previous fetal surgery)
• Patient does not have a support person (e.g., husband, partner, mother)
• Inability to comply with the travel and follow-up requirements of fetal surgery
• Patient does not meet other psychosocial criteria (as determined by the psychosocial interviewer) to handle the implications of fetal surgery
• Participation in another intervention study that influences maternal and fetal morbidity and mortality or participation in this trial in a previous pregnancy;
• Maternal hypertension which would increase the risk of preeclampsia or preterm delivery (including, but not limited to: uncontrolled hypertension, chronic hypertension with end organ damage and new onset hypertension in current pregnancy)
• Active COVID-19 infection at time of fetal surgery as determined by positive test

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• UC Davis Health — Sacramento

Publications

• Farmer DL, Kumar P, Reynolds E, Lee SY, Powne AB, Pivetti CD, Zwienenberg M, McLennan AS, Nolta JA, Brown EG, Saadai P, Hirose S, Wang A. Feasibility and safety of cellular therapy for in-utero repair of myelomeningocele (CuRe Trial): a first-in-human, phase 1, single-arm study. Lancet. 2026 Feb 28;407(10531):867-875. doi: 10.1016/S0140-6736(25)02466-3. PMID 41763744

Identifiers

NCT: NCT04652908 · 1617774

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗