In Utero Enzyme Replacement Therapy for Lysosomal Storage Diseases (IUERT)

In Utero Enzyme Replacement Therapy (ERT) for Prenatally Diagnosed Lysosomal Storage Disorders (LSDs).

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.

Study Overview

• Status: Recruiting
• Conditions: Wolman Disease; MPS IVA; Pompe Disease Infantile-Onset; Gaucher Disease, Type 2; MPS VI; MPS I; Gaucher Disease, Type 3; MPS II; Mps VII
• Intervention / Treatment: Drug: Aldurazyme (laronidase)

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

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Emma Canepa, MS, CCRP; Phone Number: 415-476-7255; Email: Emma.Canepa@ucsf.edu
• Study Contact Backup: Name: Tippi MacKenzie, MD; Phone Number: 415-476-4086; Email: tippi.mackenzie@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • Recruiting
      • University of California
      • Contact: Emma Canepa, MS, CCRP; Phone Number: 415-476-7255; Email: Emma.Canepa@ucsf.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: Aldurazyme (laronidase); Enzyme replacement therapy for lysosomal storage diseases; Other Names: Elaprase (idursulfase); Vimizim (elosulfase alfa); Naglazyme (galsulfase); Mepsevii (vestronidase alfa-vjbk); Lumizyme (alglucosidase alfa); Kanuma (sebelipase alfa)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Duke University
• Investigators: Principal Investigator: Tippi MacKenzie, MD, University of California, San Francisco

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Estimated): July 1, 2031
• Study Completion (Estimated): July 1, 2032

Study Registration Dates

• First Submitted: August 19, 2020
• First Submitted That Met QC Criteria: August 25, 2020
• First Posted (Actual): August 31, 2020

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 18, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Cholesterol Ester Storage Disease; Glycogen Storage Disease; Wolman Disease; Glycogen Storage Disease Type II; Gaucher Disease
• Other Study ID Numbers: 20-31520

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No