Gene Therapy with Modified Autologous Hematopoietic Stem Cells for Patients with Mucopolysaccharidosis Type IIIA

NCT04201405 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: R119861
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with MPS IIIA have a clinical disorder marked by severe and progressive brain disease and neurological symptoms due to the accumulation of undigested glycosaminoglycans in all cells of the body. This study will be the first in human clinical trial to explore the safety, tolerability and clinical efficacy of ex vivo gene therapy (autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene) in MPSIIIA patients. Following treatment with the gene therapy patients will be followed up for a minimum of 3 years.

Conditions

Mucopolysaccharidosis Type IIIA

Outcome Measures

Primary Outcomes (3)

• To evaluate the tolerability of the IMP in MPS IIIA patients: scale

  Adverse events will be recorded and graded according to an adapted Pediatric Clinical Toxicity Scale from the National Institute Allergy and Infectious Diseases (NIAID), Autoimmuno-deficiency Syndrome (AIDS) Division

  up to 3 years

• To evaluate the biological efficacy of IMP post-treatment: expression of SGSH in total leukocytes

  Measured by the expression of SGSH in total leukocytes within or above normal range at 12 months post-IMP treatment

  12 months post gene therapy

• To assess the safety of the IMP in MPS IIIA patients

  Presence of replication competent virus and integration events in the leukocytes

  up to 3 years

Secondary Outcomes (7)

• To evaluate overall survival

  up to 3 years

• To evaluate peripheral engraftment of the IMP

  within 42 days of treatments

• Change in adaptive behaviour

  up to 3 years (multiple visits)

• Change in cognitive function

  up to 3 years (multiple visits)

• Change in patient behaviour

  up to 3 years

Other Outcomes (4)

• To evaluate the effect of the IMP on heparan sulphate concentration in cerebrospinal fluid (CSF), plasma and urine

  6 months and 12 months post-IMP treatments and multiple other visits over time

• To evaluate the effect of the IMP on SGSH activity in CSF, plasma and peripheral blood mononuclear cells.

  6 months and 12 months post-IMP treatments and multiple other visits over time

• To evaluate clinical efficacy of the IMP on brain imaging biomarkers

  up to 3 years

Study Arms (1)

Haematopoietic stem cell gene therapy for MPS IIIA

EXPERIMENTAL

Open label

Drug: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene

Interventions

Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene DRUG

Autologous CD34+ haematopoietic stem cells from MPS IIIA patients will be genetically modified ex vivo using CD11b.SGSH Lentiviral vector (LV), a self-inactivating LV expressing the SGSH gene codon optimized for human use and regulated by a human CD11b myeloid-specific promoter. Cells will be cryopreserved prior to patient administration.

Haematopoietic stem cell gene therapy for MPS IIIA

Eligibility Criteria

• Age: 3 Months - 24 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Written informed consent of a legally authorized guardian(s)
• Age at baseline ≥3 months and ≤24 months
• Normal cognitive function or mild cognitive deterioration (subject has a Development Quotient (DQ) score ≥80) at baseline as determined by the Bayley Scale of Infant Development-third edition (BSID-III), cognitive domain)
• Sibling or relative of known MPS IIIA patients with rapidly progressing phenotype, or genotype associated with rapidly progressing phenotype, or presence of somatic features predictive of rapid progression
• SGSH activity ≤10% of the Lower Limit of Normal as measured in leukocytes, plus either (1) a normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in leukocytes or (2) two documented mutations in the SGSH gene.
• Medically stable and able to accommodate the protocol requirements, including travel without placing an undue burden on the patient/patient's family, as determined by the CI.

You may not qualify if:

• The subject has received stem cell, gene therapy or enzyme replacement therapy (any route of administration)
• Subject currently enrolled in other interventional clinical trials.
• Contraindications for MRI scans.
• The subject has a history of poorly controlled seizures.
• Homozygous or compound heterozygous for the S298P mutation or any other mutation known to be associated to slow-progressing phenotype.
• The subject is currently receiving psychotropic or other medications which, in the CI's opinion, would be likely to substantially confound test results.
• The subject has received any investigational medicinal product (including Genistein) within 30 days prior to the Baseline visit or is scheduled to receive any investigational medicinal product during the course of the study.
• Documented Human Immunodeficiency Virus (HIV) infection (positive HIV RNA and/or anti-p24 antibodies).
• Malignant neoplasia (except local skin cancer) or a documented history of hereditary cancer syndrome. Subjects with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Medical Monitor.
• Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia, or other serious haematological disorders.
• The subject has a medical condition or extenuating circumstance that, in the opinion of the CI, might compromise the subject's ability to comply with protocol requirements, the subject's well-being or safety, or the interpretability of the subject's clinical data.
• Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing.
• Severe behavioural disturbances due to reasons other than MPS IIIA and likely to interfere with protocol compliance, as determined by the CI.
• Known sensitivity to busulfan.
• The receipt of live vaccinations within 30 days prior to study start.

Sponsors & Collaborators

• University of Manchester: lead
• Orchard Therapeutics: collaborator
• CTI Clinical Trial and Consulting Services: collaborator
• University College, London: collaborator
• Great Ormond Street Hospital for Children NHS Foundation Trust: collaborator
• Manchester University NHS Foundation Trust: collaborator

Study Sites (1)

Manchester University NHS Foundation Trust

Manchester, M13 9WL, United Kingdom

Location

Related Publications (5)

• Ellison SM, Liao A, Wood S, Taylor J, Youshani AS, Rowlston S, Parker H, Armant M, Biffi A, Chan L, Farzaneh F, Wynn R, Jones SA, Heal P, Gaspar HB, Bigger BW. Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. Mol Ther Methods Clin Dev. 2019 Apr 6;13:399-413. doi: 10.1016/j.omtm.2019.04.001. eCollection 2019 Jun 14.

  PMID: 31044143 BACKGROUND

• Holley RJ, Wood SR, Bigger BW. Delivering Hematopoietic Stem Cell Gene Therapy Treatments for Neurological Lysosomal Diseases. ACS Chem Neurosci. 2019 Jan 16;10(1):18-20. doi: 10.1021/acschemneuro.8b00408. Epub 2018 Aug 23.

  PMID: 30136572 BACKGROUND

• Ghosh A, Shapiro E, Rust S, Delaney K, Parker S, Shaywitz AJ, Morte A, Bubb G, Cleary M, Bo T, Lavery C, Bigger BW, Jones SA. Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III. Orphanet J Rare Dis. 2017 Jun 26;12(1):117. doi: 10.1186/s13023-017-0675-4.

  PMID: 28651568 BACKGROUND

• Sergijenko A, Langford-Smith A, Liao AY, Pickford CE, McDermott J, Nowinski G, Langford-Smith KJ, Merry CL, Jones SA, Wraith JE, Wynn RF, Wilkinson FL, Bigger BW. Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. Mol Ther. 2013 Oct;21(10):1938-49. doi: 10.1038/mt.2013.141. Epub 2013 Jun 7.

  PMID: 23748415 BACKGROUND

• Langford-Smith A, Wilkinson FL, Langford-Smith KJ, Holley RJ, Sergijenko A, Howe SJ, Bennett WR, Jones SA, Wraith J, Merry CL, Wynn RF, Bigger BW. Hematopoietic stem cell and gene therapy corrects primary neuropathology and behavior in mucopolysaccharidosis IIIA mice. Mol Ther. 2012 Aug;20(8):1610-21. doi: 10.1038/mt.2012.82. Epub 2012 May 1.

  PMID: 22547151 BACKGROUND

MeSH Terms

Conditions

Mucopolysaccharidosis III

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

Study Officials

• Brian Bigger

  The University of Manchester

  PRINCIPAL INVESTIGATOR

• Robert Wynn

  MFT

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 5, 2019
• First Posted: December 17, 2019
• Study Start: January 7, 2020
• Primary Completion: October 30, 2024
• Study Completion (Estimated): October 30, 2026
• Last Updated: March 30, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)