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

NCT03488394 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: 2024-514870-29-00
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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

Conditions

Mucopolysaccharidosis IH

Keywords

Mucopolysaccharidosis IH; Gene Therapy; Transplantation, Autologous; Lentiviral vector

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (7)

• Anti-IDUA antibody immune response

  Assessed at multiple timepoints up to 8 years post-treatment

• Achievement of supraphysiologic IDUA activity in blood

  Assessed at multiple timepoints up to 8 years post-treatment

• IDUA activity in plasma

  Assessed at multiple timepoints up to 8 years post-treatment

• Engraftment of transduced cells ≥ 0.30 VCN/genome

  Assessed at multiple timepoints up to 8 years post-treatment

• Normalization of urinary GAGs

  Assessed at multiple timepoints up to 8 years post-treatment

Study Arms (1)

Treatment

EXPERIMENTAL

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.

Interventions

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. 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.

Treatment

Eligibility Criteria

• Age: 28 Days - 11 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Orchard Therapeutics: lead
• Fondazione Telethon: collaborator

Study Sites (1)

Ospedale San Raffaele

Milan, 20132, Italy

Location

Related Publications (13)

• 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.

  PMID: 25708213 BACKGROUND

• 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.

  PMID: 23845948 BACKGROUND

• 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.

  PMID: 22923692 BACKGROUND

• 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.

  PMID: 19892975 BACKGROUND

• 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.

  PMID: 22458355 BACKGROUND

• 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.

  PMID: 23348427 BACKGROUND

• 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.

  PMID: 16732270 BACKGROUND

• 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.

  PMID: 15128891 BACKGROUND

• 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.

  PMID: 26095521 BACKGROUND

• 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.

  PMID: 20847202 BACKGROUND

• 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.

  PMID: 14676543 BACKGROUND

• 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.

  PMID: 3124802 BACKGROUND

• 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.

  PMID: 34788506 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis I

Interventions

Clinical Coding

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Forms and Records Control; Office Management; Practice Management; Professional Practice; Organization and Administration; Health Services Administration; Medical Records; Records; Data Collection; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Epidemiologic Methods; Public Health; Environment and Public Health

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 22, 2018
• First Posted: April 5, 2018
• Study Start: May 11, 2018
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): March 1, 2028
• Last Updated: December 9, 2025

Record last verified: 2025-12

Locations

IT (1)