Clinical trial NCT03488394: Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant
Official 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Mucopolysaccharidosis IH
Keywords: Mucopolysaccharidosis IH
Gene Therapy
Transplantation, Autologous
Lentiviral vector
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
Collaborators: name: Fondazione Telethon
First posted: 2018-04-05
Enrollment: 8
Sex: ALL
Minimum age (years): 28
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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)

Primary outcomes:
measure: Overall survival
timeFrame: 5 year
measure: Achievement of haematological engraftment
timeFrame: within day +45 after gene therapy
measure: Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability
timeFrame: 0-24 hours from injection
measure: Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus
timeFrame: 0-5 years after gene therapy
measure: Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation
timeFrame: 0-5 years after gene therapy
measure: Overall safety and tolerability (AE)
timeFrame: 0-5 years after gene therapy
measure: IDUA activity in blood
timeFrame: 1, 3 and 5 years post treatment
Secondary outcomes:
measure: Anti-IDUA antibody immune response
timeFrame: 0-5 years after gene therapy
measure: Achievement of supraphysiologic IDUA activity in blood
timeFrame: 1, 3 and 5 years after gene therapy
measure: IDUA activity in plasma
timeFrame: 1, 3 and 5 years after gene therapy
measure: Engraftment of transduced cells at levels above 30%
timeFrame: by year 1 and after 3 and 5 years from gene therapy
measure: Normalization of urinary GAGs
timeFrame: 1, 3 and 5 years after gene therapy
measure: Normalization of spleen and liver
timeFrame: 1, 3 and 5 years after gene therapy
measure: Growth velocity
timeFrame: 1, 3 and 5 years after gene therapy
Other outcomes:
Locations:
city: Milano
country: Italy
facility: Ospedale San Raffaele
Study officials:
References:
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