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| Name | Class |
|---|---|
| Duke University | OTHER |
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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Aldurazyme (laronidase) | Drug | Enzyme replacement therapy for lysosomal storage diseases |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants that show measured levels of antibodies against the enzyme. | Laboratory analysis of blood to measure antibody levels. | 6 years |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants that show functional cardiac, growth, mobility, and neurocognitive function. | ecogardiogram, skeletal survey, neurocognitve assessments such as Bayley III to assess cardiac, growth, mobility and neurocognitive function. | 6 years |
Inclusion Criteria:
Exclusion Criteria:
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:
Mother will require therapeutic dosing of anticoagulation within 24 hours prior to or following the intervention.
Maternal pregnant women of age 18-50, carrying a male or female fetus at 18 0/7 weeks to 34 6/7 weeks.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Tippi MacKenzie, MD | Contact | 415-476-4086 | tippi.mackenzie@ucsf.edu | |
| Emma Canepa, MS, CCRP | Contact | 415-476-7255 | Emma.Canepa@ucsf.edu |
| Name | Affiliation | Role |
|---|---|---|
| Tippi MacKenzie, MD | University of California, San Francisco | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California | Recruiting | San Francisco | California | 94158 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32102934 | Result | 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. | |
| 30337566 |
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| 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. |
| 9918480 | 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. |
| 15324318 | 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. |
| 23510062 | Result | Rosenbloom BE, Weinreb NJ. Gaucher disease: a comprehensive review. Crit Rev Oncog. 2013;18(3):163-75. doi: 10.1615/critrevoncog.2013006060. |
| 19948615 | 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. |
| 28374935 | 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. |
| 28657663 | 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. |
| 21637107 | 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. |
| 39891377 | Derived | 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. |
| 37955580 | 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. |
| ID | Term |
|---|---|
| D013398 | Sudden Infant Death |
| D009085 | Mucopolysaccharidosis IV |
| D009087 | Mucopolysaccharidosis VI |
| D016538 | Mucopolysaccharidosis VII |
| D005776 | Gaucher Disease |
| D015223 | Wolman Disease |
| ID | Term |
|---|---|
| D003645 | Death, Sudden |
| D003643 | Death |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D066088 | Infant Death |
| D009083 | Mucopolysaccharidoses |
| D002239 | Carbohydrate Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D016464 | Lysosomal Storage Diseases |
| D017520 | Mucinoses |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D013106 | Sphingolipidoses |
| D020140 | Lysosomal Storage Diseases, Nervous System |
| D020739 | Brain Diseases, Metabolic, Inborn |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008064 | Lipidoses |
| D008052 | Lipid Metabolism, Inborn Errors |
| D052439 | Lipid Metabolism Disorders |
| D015217 | Cholesterol Ester Storage Disease |
| D007232 | Infant, Newborn, Diseases |
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| ID | Term |
|---|---|
| D007068 | Iduronidase |
| C517982 | idursulfase |
| C102295 | GALNS protein, human |
| C508864 | galsulfase |
| C000654126 | vestronidase alfa |
| C509951 | GAA protein, human |
| C000603932 | Sebelipase alfa |
| ID | Term |
|---|---|
| D006026 | Glycoside Hydrolases |
| D006867 | Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
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