TigetT10_MPSIH: Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant
Study Details
Study Description
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment 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.
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.
|
Outcome Measures
Primary Outcome Measures
- Overall survival [5 year]
Number of subjects alive at the end of the trial
- Achievement of haematological engraftment [within day +45 after gene therapy]
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).
- Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Short term tolerability [0-24 hours from injection]
Percentage of subjects not experiencing short-term adverse events of any grade and systemic reactions
- Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of Replication Competent Lentivirus [0-5 years after gene therapy]
Percentage of subjects without Replication Competent Lentivirus
- Safety of the administration of autologous haematopoietic stem cells transduced with IDUA LV - Absence of malignancy or abnormal clonal proliferation [0-5 years after gene therapy]
Percentage of subjects without abnormal clonal proliferation
- Overall safety and tolerability (AE) [0-5 years after gene therapy]
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.
- IDUA activity in blood [1, 3 and 5 years post treatment]
IDUA activity measured on peripheral blood dried spot
Secondary Outcome Measures
- Anti-IDUA antibody immune response [0-5 years after gene therapy]
Presence and titer of anti-IDUA antibody on serum
- Achievement of supraphysiologic IDUA activity in blood [1, 3 and 5 years after gene therapy]
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.
- IDUA activity in plasma [1, 3 and 5 years after gene therapy]
IDUA activity measured on plasma samples from peripheral blood.
- Engraftment of transduced cells at levels above 30% [by year 1 and after 3 and 5 years from gene therapy]
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
- Normalization of urinary GAGs [1, 3 and 5 years after gene therapy]
Proportion of subjects achieving normalization of urinary GAG levels (heparansulfate and dermatansulfate) measured by HPLC
- Normalization of spleen and liver [1, 3 and 5 years after gene therapy]
Proportion of subjects achieving normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound
- Growth velocity [1, 3 and 5 years after gene therapy]
length/height for age and cm/year percentiles
Eligibility Criteria
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
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Lansky index >80%
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Indication to hematopoietic stem cell transplant
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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).
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Adequate cardiac, renal, hepatic and pulmonary functions
Exclusion Criteria:
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Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
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Severe, active viral, bacterial or fungal infection at eligibility evaluation
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Patients affected by neoplasia or family history of familial cancer syndromes
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Cytogenetic alterations associated with high risk of developing hematological malignancies
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History of uncontrolled seizures
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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
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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
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Patients with DQ/IQ <70
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Previous allogeneic hematopoietic stem cells transplantation or gene therapy with a different product
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Contraindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Ospedale San Raffaele | Milano | Italy | 20132 |
Sponsors and Collaborators
- IRCCS San Raffaele
- Fondazione Telethon
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
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- Capotondo A, Milazzo R, Politi LS, Quattrini A, Palini A, Plati T, Merella S, Nonis A, di Serio C, Montini E, Naldini L, Biffi A. Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15018-23. doi: 10.1073/pnas.1205858109. Epub 2012 Aug 23.
- Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009 Nov 6;326(5954):818-23. doi: 10.1126/science.1171242.
- Hong KT, Kang HJ, Kim NH, Kim MS, Lee JW, Kim H, Park KD, Shin HY, Ahn HS. Successful mobilization using a combination of plerixafor and G-CSF in pediatric patients who failed previous chemomobilization with G-CSF alone and possible complications of the treatment. J Hematol Oncol. 2012 Mar 30;5:14. doi: 10.1186/1756-8722-5-14.
- Martin HR, Poe MD, Provenzale JM, Kurtzberg J, Mendizabal A, Escolar ML. Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy. Biol Blood Marrow Transplant. 2013 Apr;19(4):616-24. doi: 10.1016/j.bbmt.2013.01.010. Epub 2013 Jan 22.
- Montini E, Cesana D, Schmidt M, Sanvito F, Ponzoni M, Bartholomae C, Sergi Sergi L, Benedicenti F, Ambrosi A, Di Serio C, Doglioni C, von Kalle C, Naldini L. Hematopoietic stem cell gene transfer in a tumor-prone mouse model uncovers low genotoxicity of lentiviral vector integration. Nat Biotechnol. 2006 Jun;24(6):687-96. Epub 2006 May 28.
- Muenzer J, Fisher A. Advances in the treatment of mucopolysaccharidosis type I. N Engl J Med. 2004 May 6;350(19):1932-4.
- Shapiro EG, Nestrasil I, Rudser K, Delaney K, Kovac V, Ahmed A, Yund B, Orchard PJ, Eisengart J, Niklason GR, Raiman J, Mamak E, Cowan MJ, Bailey-Olson M, Harmatz P, Shankar SP, Cagle S, Ali N, Steiner RD, Wozniak J, Lim KO, Whitley CB. Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment. Mol Genet Metab. 2015 Sep-Oct;116(1-2):61-8. doi: 10.1016/j.ymgme.2015.06.002. Epub 2015 Jun 17.
- Visigalli I, Delai S, Politi LS, Di Domenico C, Cerri F, Mrak E, D'Isa R, Ungaro D, Stok M, Sanvito F, Mariani E, Staszewsky L, Godi C, Russo I, Cecere F, Del Carro U, Rubinacci A, Brambilla R, Quattrini A, Di Natale P, Ponder K, Naldini L, Biffi A. Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. Blood. 2010 Dec 9;116(24):5130-9. doi: 10.1182/blood-2010-04-278234. Epub 2010 Sep 16.
- Weisstein JS, Delgado E, Steinbach LS, Hart K, Packman S. Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation. J Pediatr Orthop. 2004 Jan-Feb;24(1):97-101.
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