Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies. Postnatal treatment of lysosomal diseases is well-known and well-accepted as a standard of care for Lysosomal storage disorders (LSDs).This current review evaluates the safety and feasibility of intrauterine enzyme replacement therapy (IUERT) as a novel approach to treating LSDs.

Automated summary

Lysosomal storage disorders (LSDs) are a group of monogenic conditions characterized by enzyme deficiency and substrate accumulation in lysosomes. Postnatal enzyme replacement therapy (ERT) is the standard treatment, but has limitations. In utero enzyme replacement therapy (IUERT) offers advantages such as early intervention, access to CNS, and potential immune tolerance, but fetal procedures have challenges and limitations.