Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant

Study Overview
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Brief Summary
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This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem and progenitor cells genetically modified with IDUA lentiviral vector encoding for the human α-L-iduronidase gene for the treatment of patients affected by Mucopolysaccharidosis Type I, Hurler variant

Detailed Description
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Pediatric patients with mucopolysaccharidosis type I will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow if mobilization is not feasible) and transduced with IDUA lentiviral vector encoding for the human α-L-iduronidase gene. Patients will be followed for 5 years after gene therapy. After completing participation in this study, subjects will be offered enrollment into an approved long term follow-up (LTFU) study which will enable continued follow-up for up to 15 years post-treatment (per regulatory guidelines for follow up of patients treated with ATMPs).

Official Title
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Phase I/II Study Evaluating Safety and Efficacy of Autologous Hematopoietic Stem and Progenitor Cells Genetically Modified With IDUA Lentiviral Vector Encoding for the Human α-L-iduronidase Gene for the Treatment of Patients Affected by Mucopolysaccharidosis Type I, Hurler Variant

Conditions
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Mucopolysaccharidosis IH

Intervention / Treatment
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* Genetic: Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent by parent/legal guardian Sex: Males and Females Age: ≥ 28 days and ≤ 11 years old Biochemically and molecularly proven MPS IH Lansky index >80% Indication to hematopoietic stem cell transplant Lack of a non-heterozygous (for mutated IDUA) HLA-matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5 x 10^7 Total Nucleated Cells (TNC)/Kg after 1-month search.(This criterion will not apply to patients whose country of origin does not offer unrelated donor cord blood transplantion). Adequate cardiac, renal, hepatic and pulmonary functions Exclusion Criteria: Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents) Severe, active viral, bacterial or fungal infection at eligibility evaluation Patients affected by neoplasia or family history of familial cancer syndromes Cytogenetic alterations associated with high risk of developing hematological malignancies History of uncontrolled seizures Patients with end-organ damage or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or Treponema Pallidum or Mycoplasma active infection Patients with DQ/IQ <70 Previous allogeneic hematopoietic stem cells transplantation or gene therapy with a different product Contraindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 11 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Gene therapy (autologous, CD34+ cell enriched cells fraction containing HSCs, transduced with the IDUA LV encoding for the human IDUA gene and cryopreserved in cryoformulation medium) | Genetic: Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.<br>* The drug product target dose is more or equal to 8x10^6 CD34+ cells/Kg, with a minimum dose of 4x10^6 CD34+ cells/Kg and a maximum dose of 35x10^6 CD34+ cells/Kg. The product will be injected intravenously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Number of subjects alive at the end of the trial | 5 year | 
| Achievement of haematological engraftment | First day of neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 on 3 consecutive days (in the absence of transfusions). | within day +45 after gene therapy | 
| Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability | Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions | 0-24 hours from injection | 
| Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus | Percentage of subjects without Replication Competent Lentivirus | 0-5 years after gene therapy | 
| Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation | Percentage of subjects without abnormal clonal proliferation | 0-5 years after gene therapy | 
| Overall safety and tolerability (AE) | The number of AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) and the percentage of subjects experiencing AEs (expected/unexpected and/or related/not related) and SAEs (expected/unexpected and/or related/not related) will be summarized by severity and within body system involved. Narratives will also be presented. The rate of occurrence of these events will also be estimated. | 0-5 years after gene therapy | 
| IDUA activity in blood | IDUA activity measured on peripheral blood dried spot | 1, 3 and 5 years post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-IDUA antibody immune response | Presence and titer of anti-IDUA antibody on serum | 0-5 years after gene therapy | 
| Achievement of supraphysiologic IDUA activity in blood | IDUA activity measured on peripheral blood dried spot up to supraphysiologic levels as compared with healthy donors. A supraphysiologic IDUA level is defined as >24.31 μmol/L/h, which is the 97.5 percentile of the IDUA distribution in healthy children. | 1, 3 and 5 years after gene therapy | 
| IDUA activity in plasma | IDUA activity measured on plasma samples from peripheral blood. | 1, 3 and 5 years after gene therapy | 
| Engraftment of transduced cells at levels above 30% | Engraftment will be assessed by vector-specific quantitative PCR on peripheral blood mononuclear cells (PBMC) and/or bone marrow (BM). Adequate engraftment is defined as ≥ 0.30 VCN/genome | by year 1 and after 3 and 5 years from gene therapy | 
| Normalization of urinary GAGs | Proportion of subjects achieving normalization of urinary GAG levels (heparansulfate and dermatansulfate) measured by HPLC | 1, 3 and 5 years after gene therapy | 
| Normalization of spleen and liver | Proportion of subjects achieving normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound | 1, 3 and 5 years after gene therapy | 
| Growth velocity | length/height for age and cm/year percentiles | 1, 3 and 5 years after gene therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucopolysaccharidosis IH, Gene Therapy, Transplantation, Autologous, Lentiviral vector