MPS IPhase 1PEARLNCT04532047
PEARL (PrEnAtal Enzyme Replacement Therapy for Lysosomal Storage Disorders)
A Phase 1 study testing Aldurazyme (laronidase) in people with MPS I and MPS II, run by University of California, San Francisco at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 years, women only
- What is being tested?
- Aldurazyme (laronidase)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jul 2021to 31 Jul 2032
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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
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- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of California
San Francisco, California, 94158
Emma Canepa, MS, CCRP, 415-476-7255, Emma.Canepa@ucsf.edu
About this study
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.
Read the 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
- Being tested
- Aldurazyme (laronidase)
- Medical subject headings
- Sudden Infant Death, Mucopolysaccharidosis IV, Mucopolysaccharidosis VI, Mucopolysaccharidosis VII, Gaucher Disease, Wolman Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Aldurazyme (laronidase)Drug
Also called Elaprase (idursulfase), Vimizim (elosulfase alfa), Naglazyme (galsulfase), Mepsevii (vestronidase alfa-vjbk)
Enzyme replacement therapy for lysosomal storage diseases
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Aldurazyme (laronidase) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 6 years
Number of participants with the presence and levels of glycosaminoglycans (GAGs) in urine.
Laboratory analysis of urine for GAG levels.
Measured: 6 years
The number of participants with improvement or resolution of hydrops (if present).
Improvement of hydrops via ultrasound and echocardiogram results (if present).
Measured: 6 years
Secondary outcomes (1)
Number of participants that show measured levels of antibodies against the enzyme.
Laboratory analysis of blood to measure antibody levels.
Measured: 6 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Aug 2020
- Study start1 Jul 2021
- Primary completion31 Jul 2031 (estimated)
- Study completion31 Jul 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for MPS IStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Duke University
- Responsible party
- Principal investigator, Tippi Mackenzie, University of California, San Francisco
- Investigators
- Tippi MacKenzie, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04532047
- Sponsor's protocol ID
- 20-31520
- Acronym
- PEARL
- Status last verified
- Mar 2026
- First submitted
- 19 Aug 2020
- Last updated
- 17 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 32102934Platt 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.
PubMed 30337566Meikle 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.
PubMed 9918480Azevedo 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.
PubMed 15324318Rosenbloom BE, Weinreb NJ. Gaucher disease: a comprehensive review. Crit Rev Oncog. 2013;18(3):163-75. doi: 10.1615/critrevoncog.2013006060.
PubMed 23510062Chien 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.
PubMed 19948615Blitz 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.
PubMed 28374935Tsai 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.
PubMed 28657663Banugaria 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.
PubMed 21637107Borges 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.
PubMed 39891377Herzeg 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.
PubMed 37955580