Clinical trial NCT04532047: PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
Official title: PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: MPS I
MPS II
MPS IVA
MPS VI
Mps VII
Gaucher Disease, Type 2
Gaucher Disease, Type 3
Pompe Disease Infantile-Onset
Wolman Disease
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Duke University
First posted: 2020-08-31
Enrollment: 10
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: For detailed information, please view our study website: https://pearltrial.ucsf.edu/

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

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 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:

  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.

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
timeFrame: 6 years
measure: 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.
timeFrame: 6 years
measure: Number of participants with the presence and levels of glycosaminoglycans (GAGs) in urine.
timeFrame: 6 years
measure: The number of participants with improvement or resolution of hydrops (if present).
timeFrame: 6 years
Secondary outcomes:
measure: Number of participants that show measured levels of antibodies against the enzyme.
timeFrame: 6 years
Other outcomes:
measure: Number of participants that show functional cardiac, growth, mobility, and neurocognitive function.
timeFrame: 6 years
Locations:
city: San Francisco
country: United States
facility: University of California
state: California
Study officials:
affiliation: University of California, San Francisco
name: Tippi MacKenzie, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nguyen QH, Witt RG, Wang B, Eikani C, Shea J, Smith LK, Boyle G, Cadaoas J, Sper R, MacKenzie JD, Villeda S, MacKenzie TC. Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII. Sci Transl Med. 2020 Feb 26;12(532):eaay8980. doi: 10.1126/scitranslmed.aay8980.
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