PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
NCT ID: NCT04532047
Last Updated: 2025-03-11
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE1
10 participants
INTERVENTIONAL
2021-07-01
2032-07-31
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.
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Detailed Description
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This is a phase 1 clinical trial to determine the safety and feasibility of fetal enzyme replacement therapy in fetuses with LSD
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Experimental: in utero enzyme replacement therapy
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.
Aldurazyme (laronidase)
Enzyme replacement therapy for lysosomal storage diseases
Interventions
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Aldurazyme (laronidase)
Enzyme replacement therapy for lysosomal storage diseases
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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 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
FEMALE
No
Sponsors
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Duke University
OTHER
University of California, San Francisco
OTHER
Responsible Party
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Tippi Mackenzie
Professor of Surgery
Principal Investigators
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Tippi MacKenzie, MD
Role: PRINCIPAL_INVESTIGATOR
University of California, San Francisco
Locations
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University of California
San Francisco, California, United States
Countries
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Central Contacts
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Facility Contacts
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References
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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.
Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Author Correction: Lysosomal storage diseases. Nat Rev Dis Primers. 2018 Oct 18;4(1):36. doi: 10.1038/s41572-018-0037-0.
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20;281(3):249-54. doi: 10.1001/jama.281.3.249.
Azevedo AC, Schwartz IV, Kalakun L, Brustolin S, Burin MG, Beheregaray AP, Leistner S, Giugliani C, Rosa M, Barrios P, Marinho D, Esteves P, Valadares E, Boy R, Horovitz D, Mabe P, da Silva LC, de Souza IC, Ribeiro M, Martins AM, Palhares D, Kim CA, Giugliani R. Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI. Clin Genet. 2004 Sep;66(3):208-13. doi: 10.1111/j.1399-0004.2004.00277.x.
Rosenbloom BE, Weinreb NJ. Gaucher disease: a comprehensive review. Crit Rev Oncog. 2013;18(3):163-75. doi: 10.1615/critrevoncog.2013006060.
Chien YH, Lee NC, Thurberg BL, Chiang SC, Zhang XK, Keutzer J, Huang AC, Wu MH, Huang PH, Tsai FJ, Chen YT, Hwu WL. Pompe disease in infants: improving the prognosis by newborn screening and early treatment. Pediatrics. 2009 Dec;124(6):e1116-25. doi: 10.1542/peds.2008-3667.
Blitz MJ, Rochelson B, Sood M, Bialer MG, Vohra N. Prenatal sonographic findings in a case of Wolman's disease. J Clin Ultrasound. 2018 Jan;46(1):66-68. doi: 10.1002/jcu.22481. Epub 2017 Apr 4.
Tsai AC, Hung YW, Harding C, Koeller DM, Wang J, Wong LC. Next generation deep sequencing corrects diagnostic pitfalls of traditional molecular approach in a patient with prenatal onset of Pompe disease. Am J Med Genet A. 2017 Sep;173(9):2500-2504. doi: 10.1002/ajmg.a.38333. Epub 2017 Jun 28.
Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, Chen YT, Rosenberg AS, Kishnani PS. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med. 2011 Aug;13(8):729-36. doi: 10.1097/GIM.0b013e3182174703.
Borges B, Canepa E, Chang IJ, Herzeg A, Lianoglou B, Kishnani PS, Harmatz P, MacKenzie TC, Cohen JL. Prenatal Delivery of Enzyme Replacement Therapy to Fetuses Affected by Early-Onset Lysosomal Storage Diseases. Am J Med Genet C Semin Med Genet. 2025 Jan 31:e32132. doi: 10.1002/ajmg.c.32132. Online ahead of print.
Herzeg A, Borges B, Lianoglou BR, Gonzalez-Velez J, Canepa E, Munar D, Young SP, Bali D, Gelb MH, Chakraborty P, Kishnani PS, Harmatz P, Cohen JL, MacKenzie TC. Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects. Prenat Diagn. 2023 Dec;43(13):1638-1649. doi: 10.1002/pd.6460. Epub 2023 Nov 13.
Other Identifiers
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20-31520
Identifier Type: -
Identifier Source: org_study_id
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