In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases

Brief Title

In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases

Official Title

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

Brief Summary

      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

      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

Study Phase

Phase 1

Study Type


Primary Outcome

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.

Secondary Outcome

 Number of participants that show measured levels of antibodies against the enzyme.




Aldurazyme (laronidase)

Study Arms / Comparison Groups

 Experimental: in utero enzyme replacement therapy
Description:  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.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

April 7, 2021

Completion Date

April 2032

Primary Completion Date

April 2031

Eligibility Criteria

        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

        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:

               1. inability to complete the procedure secondary to maternal body habitus or
                  placental location

               2. significant cardiopulmonary disease

               3. mirror syndrome

               4. end organ failure

               5. altered mental status

               6. placental abruption

               7. active preterm labor

               8. preterm premature rupture of membranes.

          -  Mother will require therapeutic dosing of anticoagulation within 24 hours prior to or
             following the intervention.




18 Years - 50 Years

Accepts Healthy Volunteers



Tippi MacKenzie, MD, 415-476-4086, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

University of California, San Francisco


 Duke University

Study Sponsor

Tippi MacKenzie, MD, Principal Investigator, University of California, San Francisco

Verification Date

April 2022