PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)

Because fetuses with these LSDs are at increased risk of serious perinatal morbidity and mortality, particularly in the setting of Non-Immune Hydrops Fetalis (NIHF), the administration of the approved enzyme therapy in utero has the potential to significantly improve outcomes for affected fetuses. The perinatal death rate associated with NIHF ranges from 30 to 75%, so development of an in utero approach to treatment could be of significant benefit. The in utero period has been shown to be a time of relative fetal tolerance to immune stimuli, and this tolerance may lead to improved response to ERT in situations where postnatal initiation instead leads to antibody development and impaired response to treatment. It is also probable that in some cases, initiation of ERT in utero leads to improved neurodevelopmental outcomes if the replaced enzyme impacts the neurologic system during critical periods of development.

This is a phase 1 clinical trial to determine the safety and feasibility of fetal enzyme replacement therapy in fetuses with LSD

Inclusion criteria

• Live male or female fetuses at 18 0/7 weeks to 34 6/7 weeks gestation
• Diagnosis of one of the 8 included LSDs in utero by genetic or enzymatic analyses performed on amniotic fluid, fetal blood, placental tissue, or other samples through chorionic villus sampling (CVS), amniocentesis, cordocentesis, cell free fetal DNA, or other procedures. In the event that parents are identified as genetic carriers for a LSD, diagnostic testing for the fetus would be performed to confirm the diagnosis
• Pregnant women age 18 years to 50 years, carrying a live male or female fetus at 18 0/7 weeks to 34 6/7 weeks gestation
• Identified through the above listed means to be carrying a fetus with an LSD.
• Ability to give written informed consent and comply with the requirements of the study.

Exclusion criteria

• Fetuses with a concurrent severe structural anomaly
• Fetuses with an additional pathogenic genetic variant not related to the underlying LSD that contribute a significant risk of morbidity or mortality.

Hydrops fetalis will not be an exclusion criterion because ERT has the possibility of significant benefit in this situation.

• Women with one or more significant comorbidities that would preclude fetal intervention including, but not limited to:

• inability to complete the procedure secondary to maternal body habitus or placental location
• significant cardiopulmonary disease
• mirror syndrome
• end organ failure
• altered mental status
• placental abruption
• active preterm labor
• preterm premature rupture of membranes.
• Mother will require therapeutic dosing of anticoagulation within 24 hours prior to or following the intervention.