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Phase 1 Clinical Trial: Prenatal Enzyme Replacement for Lysosomal Storage Diseases


What are lysosomal storage diseases?

Lysosomal storage diseases (LSDs) are rare, inherited metabolic disorders that are caused by mutations in genes that code for critical enzymes that break down complex molecules into simpler forms that are used or discarded by the body. Without these enzymes, toxic levels of fats, sugars, and other materials accumulate in the body’s cells. The result is severe damage to multiple organs, including the brain, heart, liver, spleen, and digestive system. While each LSD is a rare disease, collectively, LSDs affect 1 in 5,000 births worldwide.

What is the objective of the PEARL trial?

The PEARL trial is a phase 1 clinical trial of prenatal (meaning, before birth) enzyme replacement therapy (ERT) for fetuses with certain LSDs (these are listed below). The purpose of this study is to test the safety (to the fetus and the mother) and feasibility (meaning, how easy it is to do) of ERT in fetuses diagnosed with these diseases. Standard care for these diseases includes giving ERT after birth. We think there could be potential benefits to initiating ERT before birth.

Rationale for treating lysosomal storage diseases before birth

  • Prevent the development of antibodies and/or an allergic reaction to ERT. After a child has received ERT multiple times, their immune system may begin to see the medication as a foreign protein and develop antibodies against the replacement enzyme. These antibodies sometimes cause complicate the planned treatment. By introducing ERT before birth, the unique immune system of the developing fetus may be conditioned to recognize the enzyme and not see it as foreign. This could prevent the development of antibodies and/or an allergic reaction to the medicine in childhood.

  • Deliver ERT to the developing brain when the blood-brain barrier is permeable. Late in pregnancy, the blood-brain barrier begins to close to block pathogens from entering the brain. Unfortunately, the blood-brain barrier also blocks medications, so ERT given postatally does not reach the child’s brain and cannot treat the effects of the disease on the brain. ERT given before birth can cross through the fetus’ developing blood-brain barrier and into the brain. Giving ERT before birth may prevent or slow the progression of neurological damage.

  • Prevent damage to organs that begins before birth. Lysosomal storage diseases can begin to cause damage to vital organs before birth, and some fetuses do not survive to birth. By giving ERT to the fetus prenatally, we hope to improve the chances of survival and prevent damage from the disease that can begin before birth.

This is the first clinical trial in which prenatal enzyme replacement therapy will be performed in humans. Our team has treated several patients with encouraging results.

Diseases included in the PEARL trial:

  • Mucopolysaccharidosis (MPS) 1, or Hurler syndrome
  • Mucopolysaccharidosis (MPS) 2, or Hunter syndrome
  • Mucopolysaccharidosis (MPS) 4a, or Morquio syndrome
  • Mucopolysaccharidosis (MPS) 6, or Maroteaux Lamy syndrome
  • Mucopolysaccharidosis (MPS) 7, or Sly syndrome
  • Infantile-onset Pompe disease (IOPD)
  • Neuronopathic Gaucher disease (types 2 and 3)
  • Lysosomal Acid Lipase (LAL) deficiency, or Wolman disease

Trial Design


Illustration of Pearl Trial Timeline

We will enroll 10 pregnant people 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 ERT to the fetus every 2-4 weeks. This will be done by an umbilical vein injection, a procedure routinely used for in utero blood transfusions with a good safety profile. After birth, the baby will receive standard care, including ERT. We will follow the child for 5 years after birth to determine whether prenatal ERT improves long-term outcomes such as neurologic function, mobility, and growth.

Financial support for participant expenses

The study has funds to cover participant expenses for travel and the cost of research-related procedures (including the cost of traveling to San Francisco for each infusion, or temporarily relocating to San Francisco for the duration of the pregnancy). Procedures related to postnatal standard of care will be billed to participant insurance. The study team will discuss travel cost coverage and other potential costs directly with each participant prior to enrollment.

Trial Aims

  1. Determine safety of prenatal ERT to the fetus and the mother
  2. Determine feasibility of identifying and treating fetuses with prenatal ERT
  3. Determine whether prenatal ERT reduces the accumulation of toxic biomarkers (such as glycosaminoglycans)
  4. Determine whether prenatal exposure to ERT induces tolerance

Educational Information

International Registry


Trial Information

PEARL Trial website Identifier: NCT04532047

Principal Investigator: Tippi C. MacKenzie, MD

Metabolic Disease Specialist: Paul Harmatz, MD

Maternal-Fetal Medicine Specialist: Juan Gonzalez Velez, MD, MS, PhD

Clinical Research Program Manager: Emma Canepa, MS, CCRP

Genetic Counselor: Billie Lianoglou, MS, LCGC

Clinical Research Coordinator: Dane Munar


  • National Institutes for Health
  • UCSF Center for Maternal Fetal Precision Medicine