Skip to main content
SpringerLink
Log in

Prenatal Therapy for Congenital Diaphragmatic Hernia and Myelomeningocele: Advances in Particle-Based Delivery

  • Review
  • Published:
Current Stem Cell Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Prenatal intervention for congenital diseases could potentially halt or reverse devastating co-morbidities. Particle-based therapy has emerged as safe option for in-utero treatment delivery. Here, we focus on outlining the current state of knowledge regarding the application of particle-based fetal therapy in the management two structural diseases: congenital diaphragmatic hernia (CDH) and myelomeningocele (MMC).

Recent Findings

Intravenous or intra-amniotic injection of particles distribute to various tissues, including the lung, liver, and can cover surfaces such as the spine. They can be modified to target specific tissues and can carry various loads, including protein and genetic material.

Summary

In CDH, microRNA loaded particles have successfully reversed the CDH phenotype in animal models. In MMC, particle delivery has resulted in tissue growth and coverage of the spinal defect. Further research is needed for clinical translation in larger animal models and to assess long-term functional outcomes following particle-based interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data Availability

No datasets were generated or analysed during the current study.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Zu H, Gao D. Non-viral vectors in gene therapy: recent development, challenges, and prospects. AAPS J. 2021;23(4):78.

    Article  PubMed  Google Scholar 

  2. Butt MH, et al. Appraisal for the potential of viral and nonviral vectors in gene therapy: a review. Genes (Basel). 2022;13(8):1370.

    Article  CAS  PubMed  Google Scholar 

  3. Lee JH, Yeo Y. Controlled drug release from pharmaceutical nanocarriers. Chem Eng Sci. 2015;125:75–84.

    Article  CAS  PubMed  Google Scholar 

  4. Yao Y, et al. Nanoparticle-based drug delivery in cancer therapy and its role in overcoming drug resistance. Front Mol Biosci. 2020;7:193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Swingle KL, et al. Amniotic fluid stabilized lipid nanoparticles for in utero intra-amniotic mRNA delivery. J Control Release. 2022;341:616–33.

    Article  CAS  PubMed  Google Scholar 

  6. Riley RS, et al. Ionizable lipid nanoparticles for in utero mRNA delivery. Sci Adv. 2021;7(3):eaba1028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bose SK, et al. In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease. Nat Commun. 2021;12(1):4291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ricciardi AS, et al. In utero nanoparticle delivery for site-specific genome editing. Nat Commun. 2018;9(1):2481.

    Article  PubMed  PubMed Central  Google Scholar 

  9. • Deprest JA, et al. Randomized trial of fetal surgery for severe left diaphragmatic hernia. N Engl J Med. 2021;385(2):107–18. Findings from this important randomized clinical trial provided evidence that the use of FETO for CDH resulted in significant benefit over observation or expectant management alone.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Montalva L, et al. Neurodevelopmental impairment in children with congenital diaphragmatic hernia: not an uncommon complication for survivors. J Pediatr Surg. 2020;55(4):625–34.

    Article  PubMed  Google Scholar 

  11. Montalva L, Zani A. Assessment of the nitrofen model of congenital diaphragmatic hernia and of the dysregulated factors involved in pulmonary hypoplasia. Pediatr Surg Int. 2019;35(1):41–61.

    Article  PubMed  Google Scholar 

  12. Greer JJ. Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. Respir Physiol Neurobiol. 2013;189(2):232–40.

    Article  PubMed  Google Scholar 

  13. Goncalves AN, Correia-Pinto J, Nogueira-Silva C. ROBO2 signaling in lung development regulates SOX2/SOX9 balance, branching morphogenesis and is dysregulated in nitrofen-induced congenital diaphragmatic hernia. Respir Res. 2020;21(1):302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mous DS, et al. Pulmonary vascular development in congenital diaphragmatic hernia. Eur Respir Rev. 2018;27(147).

  15. Wynn J, Yu L, Chung WK. Genetic causes of congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2014;19(6):324–30.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Cushing L, et al. The roles of microRNAs and protein components of the microRNA pathway in lung development and diseases. Am J Respir Cell Mol Biol. 2015;52(4):397–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pereira-Terra P, et al. Unique tracheal fluid microRNA signature predicts response to FETO in patients with congenital diaphragmatic hernia. Ann Surg. 2015;262(6):1130–40.

    Article  PubMed  Google Scholar 

  18. Chan YC. MicroRNA regulation of angiogenesis. In: Sen CK, editor. MicroRNA in regenerative medicine. Academic Press; 2023. p. 539–72.

    Chapter  Google Scholar 

  19. • Ullrich SJ, et al. In utero delivery of miRNA induces epigenetic alterations and corrects pulmonary pathology in congenital diaphragmatic hernia. Mol Ther Nucleic Acids. 2023;32:594–602. This study shows promise that the delivery of particle therapy carrying miRNA200b reverses the CDH phenotype and is a potentially translatable treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mandl HK, et al. Optimizing biodegradable nanoparticle size for tissue-specific delivery. J Control Release. 2019;314:92–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kauffman AC, et al. Tunability of biodegradable poly(amine- co-ester) polymers for customized nucleic acid delivery and other biomedical applications. Biomacromolecules. 2018;19(9):3861–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ambegia E, et al. Stabilized plasmid-lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression. Biochim Biophys Acta. 2005;1669(2):155–63.

    Article  CAS  PubMed  Google Scholar 

  23. Gao Y, et al. Multifunctional nanoparticle for cancer therapy. MedComm (2020). 2023;4(1):e187.

    CAS  PubMed  Google Scholar 

  24. • Luks VL, et al. Surface conjugation of antibodies improves nanoparticle uptake in bronchial epithelial cells. PLoS One. 2022;17(4):e0266218. This study highlights how particles can be edited to make them tissue and cell specific.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ullrich SJ, et al. Nanoparticles for delivery of agents to fetal lungs. Acta Biomater. 2021;123:346–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Khoshgoo N, et al. MicroRNA-200b regulates distal airway development by maintaining epithelial integrity. Sci Rep. 2017;7(1):6382.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Manning SM, Jennings R, Madsen JR. Pathophysiology, prevention, and potential treatment of neural tube defects. Ment Retard Dev Disabil Res Rev. 2000;6(1):6–14.

    Article  CAS  PubMed  Google Scholar 

  28. Davis BE, et al. Long-term survival of individuals with myelomeningocele. Pediatr Neurosurg. 2005;41(4):186–91.

    Article  PubMed  Google Scholar 

  29. Farrelly JS, et al. Alginate microparticles loaded with basic fibroblast growth factor induce tissue coverage in a rat model of myelomeningocele. J Pediatr Surg. 2019;54(1):80–5.

    Article  PubMed  Google Scholar 

  30. Adzick NS, et al. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011;364(11):993–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Espinoza J, et al. Two-port, exteriorized uterus, fetoscopic meningomyelocele closure has fewer adverse neonatal outcomes than open hysterotomy closure. Am J Obstet Gynecol. 2021;225(3):327e1–9.

    Article  Google Scholar 

  32. Keil C, et al. Implementation and assessment of a laparotomy-assisted three-port fetoscopic spina bifida repair program. J Clin Med. 2023;12(15):5151.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sanz Cortes M, et al. Ambulation after in-utero fetoscopic and open spina bifida repair: predictors for ambulation at 30 months. Ultrasound Obstet Gynecol. 2024. https://doi.org/10.1002/uog.27589. Epub ahead of print. PMID: 38243917.

    Article  PubMed  Google Scholar 

  34. Watanabe M, Kim AG, Flake AW. Tissue engineering strategies for fetal myelomeningocele repair in animal models. Fetal Diagn Ther. 2015;37(3):197–205.

    Article  PubMed  Google Scholar 

  35. Dionigi B, et al. Trans-amniotic stem cell therapy (TRASCET) minimizes Chiari-II malformation in experimental spina bifida. J Pediatr Surg. 2015;50(6):1037–41.

    Article  PubMed  Google Scholar 

  36. Shieh HF, et al. Transamniotic stem cell therapy (TRASCET) in a rabbit model of spina bifida. J Pediatr Surg. 2019;54(2):293–6.

    Article  PubMed  Google Scholar 

  37. Turner CG, et al. Intra-amniotic delivery of amniotic-derived neural stem cells in a syngeneic model of spina bifida. Fetal Diagn Ther. 2013;34(1):38–43.

    Article  PubMed  Google Scholar 

  38. Chen YJ, et al. Fetal surgical repair with placenta-derived mesenchymal stromal cell engineered patch in a rodent model of myelomeningocele. J Pediatr Surg. 2017. https://doi.org/10.1016/j.jpedsurg.2017.10.040. Epub ahead of print. PMID: 29096888.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Galganski LA, et al. In utero treatment of myelomeningocele with placental mesenchymal stromal cells - selection of an optimal cell line in preparation for clinical trials. J Pediatr Surg. 2020;55(9):1941–6.

    Article  PubMed  Google Scholar 

  40. Stokes SC, et al. Impact of gestational age on neuroprotective function of placenta-derived mesenchymal stromal cells. J Surg Res. 2022;273:201–10.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wang A, et al. Placental mesenchymal stromal cells rescue ambulation in ovine myelomeningocele. Stem Cells Transl Med. 2015;4(6):659–69.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Freedman-Weiss MR, et al. Engineering alginate microparticles for optimized accumulation in fetal rat myelomeningocele. J Pediatr Surg. 2022;57(3):544–50.

    Article  PubMed  Google Scholar 

  43. Maassel NL, et al. Intra-amniotic injection of poly(lactic-co-glycolic acid) microparticles loaded with growth factor: effect on tissue coverage and cellular apoptosis in the rat model of myelomeningocele. J Am Coll Surg. 2022;234(6):1010–9.

    Article  PubMed  Google Scholar 

  44. Ching SH, Bansal N, Bhandari B. Alginate gel particles-a review of production techniques and physical properties. Crit Rev Food Sci Nutr. 2017;57(6):1133–52.

    Article  CAS  PubMed  Google Scholar 

  45. Kopac T. Protein corona, understanding the nanoparticle-protein interactions and future perspectives: a critical review. Int J Biol Macromol. 2021;169:290–301.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Current Stem Cell Reports is grateful to Dr. Graça Almeida-Porada, for her review of this manuscript.

Funding

No funding was received.

Author information

Authors and Affiliations

  1. Yale University School of Medicine, Department of Surgery, 20 York Street, FMB 107, New Haven, CT, 06510, USA

    Rachel Rivero

  2. Yale-New Haven Children’s Hospital, New Haven, CT, USA

    David H. Stitelman

Authors
  1. Rachel Rivero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David H. Stitelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Data review: R.R., D.S.; Resources: R.R., D.S.; Writing - original draft: R.R.; Writing - review & editing: R.R., D.S.

Corresponding author

Correspondence to Rachel Rivero.

Ethics declarations

Conflict of Interest

Rachel Rivero declares that she has no conflict of interest. David Stitelman is an editor for Current Stem Cell Reports. David Stitelman is an inventor on this patent. This technology is described: U.S.S.N. 62/481,562, U.S.S.N. 62/489,377, and U.S.S.N. 62/589,275.

Human and Animal Rights and Informed Consent

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted and ethical approval was obtained from Animal Care and Use Committee of Yale University.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rivero, R., Stitelman, D.H. Prenatal Therapy for Congenital Diaphragmatic Hernia and Myelomeningocele: Advances in Particle-Based Delivery. Curr Stem Cell Rep (2024). https://doi.org/10.1007/s40778-024-00237-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s40778-024-00237-8

Keywords

Search

Navigation