The fetal frontier: A review of current and emerging fetal therapies for genetic diseases

Abstract

Pivotal advancements in diagnostics have greatly improved early detection of disease in the fetus. Rapid diagnosis of prenatal disease, including many aneuploidies and single-gene disorders, is now possible. These capabilities present an opportunity for earlier interventions and involvement of multidisciplinary care for infants discovered to have genetic disorders. While advancements continue to be made surgically addressing anatomic pathologies, more recently, the scope of fetal medicine has expanded to include the treatment of genetic disease. This unique and growing group of conditions with potential prenatal therapeutic targets spans broadly to include inborn errors of metabolism, neurodegenerative disorders, hematologic conditions, and errors in hormone biosynthesis. Because many of these hereditary conditions begin exerting deleterious effects before birth, prenatal therapies are critical to minimize or potentially avoid postnatal consequences. Fetal treatments can leverage the benefits of early human development such as a selectively permissive blood-brain barrier and a naive immune system. These factors, along with a favorable vector-to-tissue mass ratio in the fetus, create ideal treatment conditions that are not present after birth. Together, improved prenatal diagnostics and safe minimally invasive approaches for the delivery of therapies in utero have opened a window to what was previously an inaccessible population: the fetal patient. This review summarizes current clinical strategies and emerging investigational approaches, including enzyme replacement, protein therapy, stem cell transplantation, and gene-targeted interventions.