PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)

NCT04532047 | Recruiting Phase 1 FDA Drug

• 1 other identifier: 20-31520
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (1)

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

  6 years

Other Outcomes (1)

• Number of participants that show functional cardiac, growth, mobility, and neurocognitive function.

  6 years

Study Arms (1)

Experimental: in utero enzyme replacement therapy

EXPERIMENTAL

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)

Interventions

Aldurazyme (laronidase) DRUG

Enzyme replacement therapy for lysosomal storage diseases

Also known as: Elaprase (idursulfase), Vimizim (elosulfase alfa), Naglazyme (galsulfase), Mepsevii (vestronidase alfa-vjbk), Lumizyme (alglucosidase alfa), Kanuma (sebelipase alfa)

Experimental: in utero enzyme replacement therapy

Eligibility Criteria

• Age: 18 Years - 50 Years
• Gender Eligibility Details: Maternal pregnant women of age 18-50, carrying a male or female fetus at 18 0/7 weeks to 34 6/7 weeks.
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Duke University: collaborator

Study Sites (1)

University of California

San Francisco, California, 94158, United States

RECRUITING

Related Publications (11)

• 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.

  PMID: 32102934 RESULT

• 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.

  PMID: 30337566 RESULT

• 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.

  PMID: 9918480 RESULT

• 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.

  PMID: 15324318 RESULT

• Rosenbloom BE, Weinreb NJ. Gaucher disease: a comprehensive review. Crit Rev Oncog. 2013;18(3):163-75. doi: 10.1615/critrevoncog.2013006060.

  PMID: 23510062 RESULT

• 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.

  PMID: 19948615 RESULT

• 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.

  PMID: 28374935 RESULT

• 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.

  PMID: 28657663 RESULT

• 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.

  PMID: 21637107 RESULT

• 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 Sep;199(3):203-217. doi: 10.1002/ajmg.c.32132. Epub 2025 Jan 31.

  PMID: 39891377 DERIVED

• 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.

  PMID: 37955580 DERIVED

MeSH Terms

Conditions

Sudden Infant Death; Mucopolysaccharidosis IV; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Gaucher Disease; Wolman Disease

Interventions

Iduronidase; idursulfase; GALNS protein, human; galsulfase; vestronidase alfa; GAA protein, human; Sebelipase alfa

Condition Hierarchy (Ancestors)

Death, Sudden; Death; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Infant Death; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Cholesterol Ester Storage Disease; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Glycoside Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes

Study Officials

• Tippi MacKenzie, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tippi MacKenzie, MD

CONTACT

415-476-4086; tippi.mackenzie@ucsf.edu

Emma Canepa, MS, CCRP

CONTACT

415-476-7255; Emma.Canepa@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Surgery

Study Record Dates

• First Submitted: August 19, 2020
• First Posted: August 31, 2020
• Study Start: July 1, 2021
• Primary Completion (Estimated): July 31, 2031
• Study Completion (Estimated): July 31, 2032
• Last Updated: March 17, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)