Annual Clinical Genetics Meeting, April 13-16, 2021

In Utero Enzyme Replacement Therapy

Phase 1 Clinical Trial: In Utero Enzyme Replacement Therapy (ERT) for Fetuses with Lysosomal Storage Diseases (LSDs)

Contact the study team: or 1-800-RX-FETUS


Lysosomal storage diseases (LSDs) are inborn errors of metabolism that are caused by a mutation coding for a critical enzyme. This causes an abnormal build-up of toxic materials throughout the body. LSDs cause severe multi-organ damage, including neurodegeneration, cardiac problems, impaired growth, and enlarged spleen and liver. While each LSD is a rare disease, collectively LSDs affect 1 in 5000 births.

This is a phase 1 clinical trial of in utero (meaning before birth) enzyme replacement therapy for fetuses with certain LSDs. The purpose of this study is to test the safety (to the fetus and the mother) and feasibility (meaning how easy is it to do) of enzyme replacement therapy in fetuses with these diseases. Standard care for these diseases involves giving enzyme replacement therapy (ERT) after birth. We believe that the potential benefits of giving ERT before birth are the following:

This is the first time in utero enzyme replacement therapy will be performed in humans. Previous studies in our lab were done in mice with a lysosomal storage disease, which showed that giving ERT before birth improved survival, decreased the effect of the disease on different parts of the body, and promoted tolerance (meaning the body did not recognize the enzyme as foreign and did not develop antibodies or an allergic reaction) compared to mice who only received ERT after birth.

Diseases included in this trial:

Trial design

Trial Design

We will enroll 10 women with a fetus diagnosed with one of the included LSDs, based on chorionic villus sampling (CVS) or amniocentesis. Between 18 to 35 weeks gestation, we will give the weight-based dose of the relevant FDA-approved enzyme replacement therapy every 2-4 weeks. This will be done by an umbilical vein injection, which is a procedure routinely used for in utero blood transfusions, and that has a good safety profile. After birth, the baby will receive standard care, including ERT and possibly stem cell transplantation (depending on the disease). We will follow the child for 5 years after birth, to determine whether in utero ERT improves long-term outcomes such as neurologic function, mobility, and growth.

Trial Aims

  1. Determine safety of in utero ERT to the fetus and the mother
  2. Determine feasibility of identifying and treating fetuses with in utero ERT
  3. Determine whether in utero ERT reduces the accumulation of toxic metabolites (glycosaminoglycans)
  4. Determine whether in utero exposure to recombinant enzyme induces tolerance

Educational Information

Nguyen QH, Witt RG, Wang B, et al. Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII. Science translational medicine. 2020;12(532). Identifier: NCT04532047

Principal Investigator: Tippi C. MacKenzie, MD

Sponsors: UCSF Center for Maternal Fetal Precision Medicine