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NCT Number: NCT03488394

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

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

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Key information

Conditions

Mucopolysaccharidosis IH Carbohydrate Metabolism, Inborn Errors Congenital, Hereditary, and Neonatal Diseases and Abnormalities Connective Tissue Diseases Genetic Diseases, Inborn Lysosomal Storage Diseases Metabolic Diseases Metabolism, Inborn Errors Mucinoses Mucopolysaccharidoses Mucopolysaccharidosis I Nutritional and Metabolic Diseases Skin and Connective Tissue Diseases

Age range

28 day–11 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Ospedale San Raffaele

Milan, 20132, Italy

About this study

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.

Participants will be followed for up to 15 years post treatment (per regulatory guidelines for follow up of patients treated with ATMPs, under this study (TigetT10_MPSIH) or via enrollment into a separate long term follow-up (LTFU) study for the overall OTL-203 Clinical Development Program, if one is set up prior to their Year 15 visit.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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 transplantation).
  • 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)

Treatment and study plan

Frozen autologous CD34+ hematopoietic stem and progenitor cells genetically modified with the lentiviral vector IDUA LVV, encoding for the α-L-iduronidase cDNA, in their final formulation medium.

Genetic

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.

Primary outcomes

  1. Overall survival

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    Number and percentage of subjects alive at the end of the trial

  2. Achievement of haematological engraftment

    Time frame: within day +45 after gene therapy

    Percentage of subjects with both neutrophil count more than 500/mm3 and platelets more than 20,000/mm3 (in the absence of platelet transfusion for seven consecutive days) on 3 consecutive blood counts in the first 45 days from ATIMP injection.

  3. Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Short term tolerability

    Time frame: 0-24 hours from ATIMP injection

    Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions

  4. Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Absence of Replication Competent Lentivirus

    Time frame: Assessed at multiple timepoints up to 8 years post-treatment, or if clinically indicated

    Percentage of subjects without Replication Competent Lentivirus

  5. Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LVV - Absence of malignancy or abnormal clonal proliferation

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    Percentage of subjects without abnormal clonal proliferation

  6. Overall safety and tolerability (AE)

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    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.

  7. IDUA activity in blood (up to supraphysiologic levels) at 1-year post-treatment

    Time frame: At 1 year post-treatment

    IDUA activity measured on peripheral dried blood spot

Secondary outcomes

  1. Anti-IDUA antibody immune response

    Time frame: Assessed at multiple timepoints up to 8 years post-treatment, or if clinically indicated

    Presence or absence and titer of anti-IDUA antibody on plasma or serum

  2. Achievement of supraphysiologic IDUA activity in blood

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    IDUA activity measured on peripheral dried blood spots up to supraphysiologic levels as compared with healthy donors. A supraphysiologic IDUA level is defined as >24.31 μmol/L/h, which is the 97.5th percentile of the IDUA distribution in healthy children

  3. IDUA activity in plasma

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    IDUA activity measured on plasma samples from peripheral blood.

  4. Engraftment of transduced cells ≥ 0.30 VCN/genome

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    Percentage of subjects with engraftment of transduced cells ≥ 0.30 VCN/genome on peripheral blood mononuclear cells (PBMC) and/or bone marrow (BM) progenitor cells.

  5. Normalization of urinary GAGs

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    Percentage of subjects achieving normalization of urinary GAG levels (heparan sulfate and dermatan sulfate) measured by HPLC

  6. Normalization of spleen and liver

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    Percentage of subjects with normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound

  7. Growth velocity

    Time frame: Assessed at multiple timepoints up to 15 years post-treatment

    Length/height for age (cm) per month vs. WHO percentiles

Sponsors and collaborators

Lead sponsor

Orchard Therapeutics

Industry

Collaborators

  • Fondazione Telethon

Registry information

Official study title

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

Acronym: TigetT10_MPSIH

Important dates

Study start
2018
Primary completion
2035
Study completion
2035
First posted
Apr 5, 2018
Registry last updated
Jul 16, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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