In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases

Study Overview
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Brief Summary
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The investigators aims to determine the the maternal and fetal safety and feasibility of in utero fetal enzyme replacement therapy in fetuses with Lysosomal Storage Diseases.

Detailed Description
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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

Official Title
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In Utero Enzyme Replacement Therapy (ERT) for Prenatally Diagnosed Lysosomal Storage Disorders (LSDs).

Conditions
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MPS I, MPS II, MPS IVA, MPS VI, Mps VII, Gaucher Disease, Type 2, Gaucher Disease, Type 3, Pompe Disease Infantile-Onset, Wolman Disease

Intervention / Treatment
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* Drug: Aldurazyme (laronidase)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental: in utero enzyme replacement therapy<br>ERT will be delivered in utero. Typically, the target of the procedure to administer in utero ERT will be the umbilical vein near the insertion of the umbilical cord into the placenta. The dose of the ERT will be dependent on the specific disease process and enzyme being replaced, and the estimated weight of the fetus. The dosage will be the same as the recommended weight-based postnatal dosing, adjusted for estimated fetal weight. IUERT will be repeated every 2-4 weeks, which is an interval consistent with the standard of care for IUTs (every 2-4 weeks) to avoid excessive access through the umbilical vein. This interval is also consistent with the half-life of each relevant enzyme. | Drug: Aldurazyme (laronidase)<br>* Enzyme replacement therapy for lysosomal storage diseases<br>* Other names: Kanuma (sebelipase alfa);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0. | Adverse and serious adverse events including, but not limited to, death within 24 hours after the procedure, stillbirth, death prior to initial hospital discharge,increased response with antibody development above that expected with postnatal ERT, and serious related or serious unexpected adverse events exceeding those expected with the natural history of treated disease during the first five years of life, assessed by CTCAE v5.0. | 6 years | 
| Number of participants to receive the full initial, weight-based dose of enzyme replacement therapy through the fetal umbilical vein, and subsequent doses throughout the pregnancy. | full dose administration compared to the need to halt the intervention prior to administration of a full dose. | 6 years | 
| Number of participants with the presence and levels of glycosaminoglycans (GAGs) in urine. | Laboratory analysis of urine for GAG levels. | 6 years | 
| The number of participants with improvement or resolution of hydrops (if present). | Improvement of hydrops via ultrasound and echocardiogram results (if present). | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants that show measured levels of antibodies against the enzyme. | Laboratory analysis of blood to measure antibody levels. | 6 years |