MT2018-18: Sleeping Beauty Transposon-Engineered Plasmablasts for Hurler Syndrome Post Allo HSCT

Study Overview
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Brief Summary
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This is a single center, Phase 1/2 study in which patients with Hurler syndrome who have previously undergone allogeneic hematopoietic stem cell transplantation are treated with autologous plasmablasts engineered to express α-L-iduronidase (IDUA) using the Sleeping Beauty transposon system.

Official Title
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Sleeping Beauty Transposon-Engineered Plasmablasts for Expression and Delivery of Alpha-L-iduronidase in Patients With Hurler Syndrome That Have Previously Undergone Allogeneic Transplantation

Conditions
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Mucopolysaccharidosis Type IH (MPS IH, Hurler Syndrome), Mucopolysaccharidosis Type IH, MPS IH, Hurler Syndrome

Intervention / Treatment
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* Drug: Autologous Plasmablasts


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Mucopolysaccharidosis type IH (MPS IH, Hurler syndrome) Underwent a previous hematopoietic stem cell transplant >1 year prior to study enrollment Age ≥3 years and ≤8 years at time of study registration ≥ 10 kilograms body weight Creatinine <1.5 normal for gender and age. Ejection fraction ≥ 40% by echocardiogram Must commit to traveling to the University of Minnesota for the necessary followup evaluations Must agree to stay in the Twin Cities area (<45-minute drive from the Masonic Children's Hospital) for a minimum of 5 days after each cell infusion Voluntary written parental consent prior to the performance of any study related procedures Exclusion Criteria: Prior enzyme replacement therapy within 4 months prior to enrolling on study History of B cell related cancer, EBV lymphoproliferative disease or autoimmune disorders Evidence of active graft vs. host disease Requirement for systemic immune suppression Requirement for continuous supplemental oxygen Any medical condition likely to interfere with assessment of safety or efficacy of the study treatment. In the investigator's judgement, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Dose Escalation<br> | Drug: Autologous Plasmablasts<br>* Autologous Plasmablasts engineered to express α-L-iduronidase (IDUA) using the Sleeping Beauty transposon system. Phase 1: Dose Level 1: 5 x 10e7 cells/kg on Day 0 Dose Level 2: 1 x 10e8 cells/kg on Day 0 Dose Level 3: 1 x 10e8 cells/kg x 2 doses on Day 0 and Day 30 +/-3 days. Phase 2: - Maximum Tolerated Dose (MTD) established in Phase I<br>* Other names: Sleeping Beauty;|
| Experimental: Phase 2 - Expansion at MTD<br> | Drug: Autologous Plasmablasts<br>* Autologous Plasmablasts engineered to express α-L-iduronidase (IDUA) using the Sleeping Beauty transposon system. Phase 1: Dose Level 1: 5 x 10e7 cells/kg on Day 0 Dose Level 2: 1 x 10e8 cells/kg on Day 0 Dose Level 3: 1 x 10e8 cells/kg x 2 doses on Day 0 and Day 30 +/-3 days. Phase 2: - Maximum Tolerated Dose (MTD) established in Phase I<br>* Other names: Sleeping Beauty;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | Maximum tolerated dose (MTD) of autologous plasmablasts engineered to express large amounts of α-L-iduronidase (IDUA) using a Sleeping Beauty transposon approach | 1 Year | 
| Growth Velocity (cm/year) | Growth velocity in centimeters/year over a one-year period through determinations of sitting and standing height at baseline and post infusion | 1 Year | 
| Safety and Tolerability after Infusion: Incidence of Adverse Events | Incidence of Adverse Events | 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Z-score Growth Rate | Estimate the 1-year Z-score growth rate standardized for age and gender | 1 Year | 
| Donor Engraftment | Estimate percent myeloid donor chimerism (CD33/66b) at baseline and at 6 and 12 months. | Baseline, 6 months and 1 Year | 
| Levels of circulating antibodies (IgG, IgM, IgA and IgE) | Determine levels of circulating antibodies (IgG, IgM, IgA and IgE) at baseline and at scheduled time points post infusion. | 1 Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MPS IH, Hurler syndrome