Gene Therapy With Modified Autologous Hematopoietic Stem Cells for the Treatment of Patients With Mucopolysaccharidosis Type I, Hurler Variant (TigetT10_MPSIH)

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Mucopolysaccharidosis IH
• Intervention / Treatment: 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.

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 8 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 Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 11 years (Child)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Number and percentage of subjects alive at the end of the trial	8 years
Achievement of haematological engraftment	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.	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 ATIMP 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	Assessed at multiple timepoints up to 8 years post-treatment
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	Assessed at multiple timepoints up to 8 years post-treatment
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.	Assessed at multiple timepoints up to 8 years post-treatment
IDUA activity in blood (up to supraphysiologic levels) at 1-year post-treatment	IDUA activity measured on peripheral blood dried spot	Assessed at multiple timepoints up to 8 years post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-IDUA antibody immune response	Presence or absence and titer of anti-IDUA antibody on serum	Assessed at multiple timepoints up to 8 years post-treatment
Achievement of supraphysiologic IDUA activity in blood	IDUA activity measured on peripheral 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	Assessed at multiple timepoints up to 8 years post-treatment
IDUA activity in plasma	IDUA activity measured on plasma samples from peripheral blood.	Assessed at multiple timepoints up to 8 years post-treatment
Engraftment of transduced cells ≥ 0.30 VCN/genome	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.	Assessed at multiple timepoints up to 8 years post-treatment
Normalization of urinary GAGs	Percentage of subjects achieving normalization of urinary GAG levels (heparan sulfate and dermatan sulfate) measured by HPLC	Assessed at multiple timepoints up to 8 years post-treatment
Normalization of spleen and liver	Percentage of subjects with normal spleen and liver assessed by clinical examination (palpation) and/or ultrasound	Assessed at multiple timepoints up to 8 years post-treatment
Growth velocity	length/height for age and cm/year percentiles	Assessed at multiple timepoints up to 8 years post-treatment

Collaborators and Investigators

• Sponsor: Orchard Therapeutics
• Collaborators: Fondazione Telethon

Publications and helpful links

General Publications

• 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, Lefrere F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougneres 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.
• Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.
• 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. doi: 10.1038/nbt1216. Epub 2006 May 28.
• 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.
• Aldenhoven M, Jones SA, Bonney D, Borrill RE, Coussons M, Mercer J, Bierings MB, Versluys B, van Hasselt PM, Wijburg FA, van der Ploeg AT, Wynn RF, Boelens JJ. Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines. Biol Blood Marrow Transplant. 2015 Jun;21(6):1106-9. doi: 10.1016/j.bbmt.2015.02.011. Epub 2015 Feb 20.
• 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.
• 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.
• Muenzer J, Fisher A. Advances in the treatment of mucopolysaccharidosis type I. N Engl J Med. 2004 May 6;350(19):1932-4. doi: 10.1056/NEJMp048084. No abstract available.
• 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. doi: 10.1097/00004694-200401000-00019.
• Wraith JE, Rogers JG, Danks DM. The mucopolysaccharidoses. Aust Paediatr J. 1987 Dec;23(6):329-34. doi: 10.1111/j.1440-1754.1987.tb00284.x.
• Gentner B, Tucci F, Galimberti S, Fumagalli F, De Pellegrin M, Silvani P, Camesasca C, Pontesilli S, Darin S, Ciotti F, Sarzana M, Consiglieri G, Filisetti C, Forni G, Passerini L, Tomasoni D, Cesana D, Calabria A, Spinozzi G, Cicalese MP, Calbi V, Migliavacca M, Barzaghi F, Ferrua F, Gallo V, Miglietta S, Zonari E, Cheruku PS, Forni C, Facchini M, Corti A, Gabaldo M, Zancan S, Gasperini S, Rovelli A, Boelens JJ, Jones SA, Wynn R, Baldoli C, Montini E, Gregori S, Ciceri F, Valsecchi MG, la Marca G, Parini R, Naldini L, Aiuti A, Bernardo ME; MPSI Study Group. Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome. N Engl J Med. 2021 Nov 18;385(21):1929-1940. doi: 10.1056/NEJMoa2106596.

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2018
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: March 22, 2018
• First Submitted That Met QC Criteria: March 28, 2018
• First Posted (Actual): April 5, 2018

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Gene Therapy; Transplantation, Autologous; Lentiviral vector; Mucopolysaccharidosis IH
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Mucopolysaccharidosis I; Professional Practice; Organization and Administration; Health Services Administration; Health Care Quality, Access, and Evaluation; Epidemiologic Methods; Data Collection; Health Care Evaluation Mechanisms; Quality of Health Care; Public Health; Environment and Public Health; Records; Practice Management; Medical Records; Forms and Records Control; Office Management; Clinical Coding
• Other Study ID Numbers: 2024-514870-29-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No