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Gene therapy has traditionally involved the delivery of exogenous genetic material to a cell-most commonly to replace defective genes causing monogenic disorders. This allows cells to produce proteins that are otherwise absent in sufficient quantities, ideally for a therapeutic purpose. Since its inception over 40 years ago, the field of gene therapy has significantly expanded and now includes targeted gene editing strategies, including, but not limited to, clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), and zinc-finger nucleases (ZFNs).

Importance Gene and stem cell therapies have become viable therapeutic options for many postnatal disorders. For select conditions, prenatal application would provide improved outcomes. The fetal state allows for several theoretical advantages over postnatal therapy, including immune immaturity and cellular niche accessibility. Observations Advances in prenatal diagnostic accuracy and surgical precision, as well as improvements in stem cell and gene therapy methods, have made prenatal gene and stem cell therapy realistic. Studies in mouse models and early human trials demonstrate the feasibility of these approaches. Additional efforts are under way to streamline fetal applications of stem cell and gene therapy while carefully considering best ethical practice and following established regulatory pathways. Conclusions and Relevance Fetal stem cell and gene therapy bring important therapeutic opportunities for select disorders that present in the fetal and neonatal periods. While this field is in its infancy, these therapies are starting to be available clinically, and clinicians should be aware of their benefits and challenges.

Asymptomatic cystic lung lesions-congenital pulmonary airway malformations (CPAMs), sequestrations, and bronchogenic cysts-are commonly diagnosed prenatally. Indications to resect are to eliminate risk of malignancy or infection. CPAMs consist of a spectrum of malformations, with type 1 historically considered the most common. Mucinous cell clusters, seen almost exclusively in type 1, are premalignant lesions at risk for progression to mucinous adenocarcinoma. We reviewed and classified 2.5 years of consecutive, prenatally diagnosed lesions as extralobar sequestration, intralobar sequestration, type 1 CPAM, type 2 CPAM/bronchial atresia, or "other" to determine the distribution of lesion types and risk of malignancy. One hundred eighty-four lesions in 174 patients showed type 1 CPAM to be least common subtype. Type 1 CPAMs had more severe presentation, infrequently had features of obstruction, and usually had cysts ≥2 cm. Fifteen of eighteen type 1 CPAMs had mucinous cell clusters (total risk, 8%), with mucous cells outside main cyst in 12/15. No pleuropulmonary blastomas were identified. Additional historic cases were reviewed to further evaluate risk of malignancy. Over 14 years, 28 infants with fetal/type 1 lesions were identified, with clusters of mucinous cells in 75% of cases. A total of 9 pleuropulmonary blastomas were diagnosed in 6 patients over 16 years. Contrary to historical studies, type 1 CPAMs are much less common than type 2, likely related to detection of asymptomatic lesions prenatally. A majority of type 1 CPAMs contain mucinous cell clusters. This data is useful in management of patients in centers that do not resect asymptomatic lesions.

OBJECTIVES The purpose of this study was to assess the need and timing of extracorporeal membrane oxygenation in relation to congenital diaphragmatic hernia repair as modifiers of short-term neurodevelopmental outcomes. DESIGN Retrospective study. SETTING A specialized tertiary care center. PATIENTS Between June 2004 and February 2016, a total of 212 congenital diaphragmatic hernia survivors enrolled in our follow-up program. Neurodevelopmental outcome was assessed at a median age of 22 months (range, 5-37) using the Bayley Scales of Infant Development, third edition. Fifty patients (24%) required extracorporeal membrane oxygenation support. Four patients (8%) were repaired prior to cannulation, 25 (50%) were repaired on extracorporeal membrane oxygenation, and 21 (42%) were repaired after decannulation. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Children with congenital diaphragmatic hernia, who required extracorporeal membrane oxygenation scored on average 4.6 points lower on cognitive composite (p = 0.031) and 9.2 points lower on the motor composite (p < 0.001). Language scores were similar between groups. Mean scores for children with congenital diaphragmatic hernia repaired on extracorporeal membrane oxygenation were significantly lower for cognition (p = 0.021) and motor (p = 0.0005) outcome. Language scores were also lower, but did not reach significance. A total of 40% of children repaired on extracorporeal membrane oxygenation scored below average in all composites, whereas only 9% of the non-extracorporeal membrane oxygenation, 4% of the repaired post-extracorporeal membrane oxygenation, and 25% of the repaired pre-extracorporeal membrane oxygenation patients scored below average across all domains. Only 20% of congenital diaphragmatic hernia survivors repaired on extracorporeal membrane oxygenation support scored within the average range for all composite domains. Duration of extracorporeal membrane oxygenation support was not associated with a higher likelihood of adverse cognitive (p = 0.641), language (p = 0.147), or motor (p = 0.720) outcome. CONCLUSIONS Need for extracorporeal membrane oxygenation in congenital diaphragmatic hernia survivors is associated with worse neurocognitive and neuromotor outcome. Need for congenital diaphragmatic hernia repair while on extracorporeal membrane oxygenation is associated with deficits in multiple domains. Overall time on extracorporeal membrane oxygenation did not impact neurodevelopmental outcome.

This review summarizes outcomes of fetal surgery for myelomeningocele (MMC) as they compare to postnatal MMC repair and provides insights into areas of investigation to improve fetal MMC repair.Recent studies confirm the findings of the Management of Myelomeningocele Study and support the decreased need for postnatal ventricular shunts, improved hindbrain herniation, and improved neurofunctional outcome following open fetal repair compared to postnatal repair at the risk of increased maternal complications and preterm birth. Larger studies of minimally invasive fetal repair demonstrate that, although technically feasible, this approach is associated with longer operative times, increased membrane complications, an earlier gestational age at birth, persistent cerebrospinal fluid leakage, and incidences of persistent postnatal hindbrain herniation resulting in death or requiring surgical decompression.Open prenatal MMC repair is a new standard of care option with improved postnatal outcomes in a highly specific patient population when performed at select multidisciplinary fetal surgery centers. More investigations are required to optimize minimally invasive approaches prior to reliable clinical application.

In utero bone marrow transplantation (IUBMT) induces donor-specific tolerance for postnatal cellular or organ transplantation. Consistent induction of tolerance requires a threshold of mixed hematopoietic chimerism (>1%). CD26 is a peptidase whose inhibition has been demonstrated to influence granulocyte colony-stimulating factor induced mobilization of hematopoietic stem cells and increase homing and engraftment of BM cells in adult transplantation models. We hypothesized that CD26 inhibition would increase the frequency and levels of allogeneic hematopoietic chimerism after IUBMT. Methods: B6 GFP BM was injected intravenously into E14 Balb/c fetal mice at a dose of 20e6 cells/fetus with or without CD26 inhibition with diprotin A. Early kinetic analysis was performed to assess donor cell homing to fetal liver (FL). Peripheral blood (PB) was analyzed up to 20 weeks after birth for donor cell chimerism and multilineage engraftment by flow cytometry. PB was also analyzed for donor cell chimerism at the same time points from Balb/c mice receiving 10e6 CD26 inhibited GFP BM cells coinjected with 10e6 noninhibited congenic B6Ly5.2 BM cells at E14 to assess for an in utero competitive advantage provided by CD26 inhibition. Results: CD26 inhibition increased donor cell homing to the FL at 24, 48 and 96 hours after injection (69.27±8.19 vs 30.21±6.44, 57.20±14.63 vs 36.80±14.20, 46.14±15.79 vs 12.09±7.01; p Conclusion: CD26 inhibition of donor BM prior to IUBMT results in an increased efficiency of donor engraftment and higher levels of chimerism. CD26 inhibition offers a potential mechanism to increase the level of engraftment and the rate of donor specific tolerance and may facilitate combined pre and postnatal strategies for cellular and organ transplantation. Figure Figure