Danielle S. Walsh

The Rationale for in utero Repair of Myelomeningocele

Objectives: Despite advances in prenatal diagnosis, management of fetal myelomeningocele has been limited to abortion or supportive postnatal care. The rationale for fetal repair of myelomeningocele and initial clinical outcomes are discussed. Methods: A complete review of the literature concerning fetal myelomeningocele and repair was performed. Results: While myelomeningocele is a primary embryologic disorder, neurologic damage is also secondary to progressive in utero damage to the exposed spinal cord. Animal models with midgestational coverage of the spinal defect demonstrate near normal neurologic function at term. Early clinical results suggest that fetal closure can salvage neurologic function, reverse hindbrain herniation, and diminish the need for ventriculoperitoneal shunting. Conclusions: In utero repair of myelomeningocele may improve neurologic outcomes and reduce hindbrain herniation in selected patients.

Myelomeningocele: prenatal diagnosis, pathophysiology and management

Myelomeningocele (MMC) is a common birth defect that is associated with significant lifelong morbidity. Little progress has been made in the postnatal surgical management of the child with spina bifida. Postnatal surgery is aimed at covering the exposed spinal cord, preventing infection, and treating hydrocephalus with a ventricular shunt. In utero repair of open spina bifida is now performed in selected patients and presents an additional therapeutic alternative for expectant mothers carrying a fetus with MMC. Early fetal intervention may improve neurologic outcome and reduce the hindbrain herniation associated with the Arnold-Chiari II malformation. These changes may improve long-term neurologic function and limit requirements for shunt placements and other surgical interventions. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in utero intervention. A prospective, randomized clinical trial is planned comparing prenatal MMC repair with postnatal repair.

Foetal surgery for spina bifida.

In utero repair of open spina bifida or myelomeningocele (MMC) is now performed in selected patients and presents an additional alternative to obstetricians and neonatologists counselling expectant mothers carrying a foetus with MMC. Early foetal intervention may improve neurologic outcomes and reduce the hindbrain herniation associated with the Arnold-Chiari II malformation in open spina bifida. These changes may improve long-term neurologic function and limit requirements for shunt placements and other surgical interventions. Further research is needed to better understand the pathophysiology of MMC, the ideal timing and technique of repair, and the long-term impact of in utero intervention. A prospective, randomized clinical trial is planned comparing prenatal MMC repair with postnatal repair.

Fetal intervention for obstructive uropathy

Obstructive uropathy is a significant source of morbidity and mortality in the neonate and infant, despite advances in postnatal management. Diagnosis is typically made early in the second trimester on the basis of sonographic measurements. In utero therapy holds promise for improved outcomes by preventing progressive urinary tract damage and permitting drainage of urine into the amniotic space to minimize the pulmonary sequelae of oligohydramnios. Multiple studies with animal models have showed the benefits of midgestational intervention, but large prospective, randomized studies have not yet been performed to confirm these findings in humans. Standardization of the diagnostic evaluation allows for refined patient selection, resulting in improved postnatal outcomes after fetal vesicoamniotic shunting. Research into the role of specific growth factors and immunoproteins in renal development and function may further improve patient selection and outcome. This article reviews diagnosis, technique, and outcomes for fetal treatment of obstructive uropathy.

Adenovirus-Mediated Ex Vivo Gene Transfer of Human Vascular Endothelial Growth Factor in a Rabbit Laryngotracheal Reconstruction Model

Free autologous cartilage, which is used in laryngotracheal reconstruction (LTR), may undergo progressive necrosis as a result of delayed revascularization. Angiogenic growth factors, such as vascular endothelial growth factor (VEGF), promote angiogenesis in the ischemic environment. We studied the effect of ex vivo gene transfer of VEGF121 on cartilage angiogenesis and graft survival in a rabbit model of LTR. Sixty rabbits underwent LTR with auricular cartilage. The grafts were treated at 1 × 109 plaque-forming units with 1) VEGF121 (n = 20), 2) LacZ reporter gene (n = 20), or 3) saline solution (n = 20). Graft neovascularization and survival were histologically assayed at 1 and 10 weeks. Angiogenesis was enhanced at both 1 and 10 weeks after treatment with VEGF121 as compared to controls (p < .001). No statistical improvement in graft survival was evident after treatment with VEGF121. Ex vivo gene transfer to cartilage may be a promising gene therapy strategy to enhance revascularization — and, potentially, cartilage survival — under the proper conditions.

The temporal course of adenovirus-mediated gene transfer in the rat larynx.

OBJECTIVE: Polypeptide growth factors have important influences on wound-healing and scar tissue formation. Specific growth factors or their inhibitors may potentially decrease scar tissue formation and prevent subglottic stenosis. Gene transfer using recombinant adenovirus may be an ideal method to mediate endogenous production of growth factors to inhibit fibrosis. STUDY DESIGN: The study incorporated adenovirus-mediated transduction of normal and stenotic rat larynges and histologic analysis of the sequential expression of a β-galactosidase marker gene over time. SETTING: The study was conducted at the animal care facility of an academic childrens hospital. RESULTS: We report successful transduction in normal and injured rat larynx with peak expression of β-galactosidase at 2 days after transduction and almost complete disappearance by 7 days. There appeared to be an early inflammatory response to the viral injection, but at 7 and 14 days after injection (transduction) the uninjured rat larynges resumed a normal histologic appearance. All distant sites stained negative for β-galactosidase. CONCLUSION: Recombinant adenovirus-mediated gene transfer is feasible in the rat larynx with transient duration and limited toxicity. SIGNIFICANCE: Adenovirus-mediated gene transfer has the potential to deliver growth factors that modulate wound healing and inflammation in the larynx by inhibiting fibrosis.