­Trans-amniotic Nucleic Acid Therapy

Background

Nucleic acids like DNA and mRNA can be customized and administered for reprogramming cell functions to treat specific disorders or for immunization. With the advances in fetal diagnosis during pregnancy and advances in gene therapy using mRNA, it became possible to design mRNA therapies to treat fetal diseases and abnormalities during this critical stage of development.

However, the administration of therapies to the fetus during pregnancy has previously relied on invasive procedures that target specific fetal blood vessels to ensure that the treatment is able to achieve fetal circulation. This mode of administration is associated with a high risk of fetal developmental abnormalities and even pregnancy loss.

Technology Overview

To combat this, Boston Children Hospital researchers studied the administration of immunoglobulins (a special class of proteins that are used to treat critical fetal disorders) through the intra-amniotic route in a minimally invasive procedure where the treatment is injected through the maternal abdomen into the peritoneal fluid that surrounds the fetus. The researchers found that this route of treatment, in addition to being associated with minimal risk to the pregnancy, has the potential to cross into fetal circulation and reach therapeutic levels.

Following this success, the team developed a novel way of packaging nucleic acids, like mRNA to be administered through this intra-amniotic route. Primary results of this work on mice provided promising possibilities for treating fetal disorders prenatally using genetic therapies, where the mRNA could reach fetal circulation and different fetal organs at different stages of fetal development. This represents the first-ever method of prenatal genetic therapy.

Applications

• Prenatal gene therapy for structural malformations like cardiac anomalies, the most common structural malformation in newborns.
• The ability to induce immunity against specific diseases prenatally using mRNA-encoded vaccines.
• Early correction of inherited metabolic disorders in the fetus that can be lethal or cause disability after birth.
• Customization of mRNA therapy for different fetal diseases that have identifiable genetic causes.

Advantages

• The intra-amniotic route of administering mRNA is minimally invasive and has a minimal risk for the pregnancy.
• Treatment of fetal disorders during fetal life can ensure the correction of structural or systematic disorders early on during development, preventing further abnormalities that might occur at more advanced stages which can be impossible to treat after birth.
• mRNA synthesis and packaging using this novel method is low cost, especially in comparison with surgical or other intensive care therapies required after birth.
• Has the potential to advance the future of precision medicine.

Publications

• Whitlock AE, Labuz DF, Kycia I, Zurakowski D, Fauza DO. Passive perinatal immunotherapy via transamniotic antibody delivery. J Pediatr Surg. 2022 Jan;57(1):52-55. doi: 10.1016/j.jpedsurg.2021.09.046. Epub 2021 Oct 5. PMID: 34756583.
• Labuz DF, Whitlock AE, Kycia I, Zurakowski D, Fauza DO. Intrauterine Growth Restriction (IUGR) as a potential target for transamniotic stem cell therapy. J Pediatr Surg. 2022 Jun;57(6):999-1003. doi: 10.1016/j.jpedsurg.2022.01.062. Epub 2022 Feb 14. PMID: 35277250.