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

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ClinicalTrials.gov Identifier: NCT04201405
Recruitment Status : Recruiting
First Posted : December 17, 2019
Last Update Posted : February 20, 2020
Sponsor:
Collaborators:
Orchard Therapeutics
CTI Clinical Trial and Consulting Services
University College, London
Great Ormond Street Hospital for Children NHS Foundation Trust
Manchester University NHS Foundation Trust
Information provided by (Responsible Party):
Rob Wynn, Manchester University NHS Foundation Trust

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.


Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis Type IIIA Drug: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene Phase 1 Phase 2

Detailed Description:

MPS IIIA is caused by a deficiency of the heparan-N-sulfatase (SGSH) enzyme, leading to the accumulation of the glycosaminoglycan heparan sulphate in the lysosomes. Untreated patients of MPS IIIA experience rapid and progressive neurologic deterioration. To date, there is no effective disease-modifying treatment for patients suffering from MPS IIIA.

This study aims to recruit 3 to 5 patients with MPS IIIA who satisfy the inclusion and exclusion criteria and provide full consent, between 3 months and 24 months of age. The investigational medicinal product (IMP) will be a cell-based gene therapy that uses genetically modified autologous CD34+ haematopoietic stem cells transduced with a lentiviral vector containing the human SGSH gene. Patients will be followed up for a minimum of 3 years after gene therapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I-II, Study of Autologous CD34+ Haematopoietic Stem Cells Transduced ex Vivo With CD11b Lentiviral Vector Encoding for Human SGSH in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIa, Sanfilippo Syndrome Type A)
Actual Study Start Date : January 7, 2020
Estimated Primary Completion Date : October 30, 2024
Estimated Study Completion Date : October 30, 2024


Arm Intervention/treatment
Experimental: Haematopoietic stem cell gene therapy for MPS IIIA
Open label
Drug: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene
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.




Primary Outcome Measures :
  1. To evaluate the tolerability of the IMP in MPS IIIA patients: scale [ Time Frame: up to 3 years ]
    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

  2. To evaluate the biological efficacy of IMP post-treatment: expression of SGSH in total leukocytes [ Time Frame: 12 months post gene therapy ]
    Measured by the expression of SGSH in total leukocytes within or above normal range at 12 months post-IMP treatment

  3. To assess the safety of the IMP in MPS IIIA patients [ Time Frame: up to 3 years ]
    Presence of replication competent virus and integration events in the leukocytes


Secondary Outcome Measures :
  1. To evaluate overall survival [ Time Frame: up to 3 years ]
    Overall survival at 36 months post IMP administration compared to natural history data

  2. To evaluate peripheral engraftment of the IMP [ Time Frame: within 42 days of treatments ]
    Measured as absence of engraftment failure or delayed hematological reconstitution within the first 6 weeks of IMP delivery. Defined as three independent and consecutive days with absolute Neutrophil Count (ANC) >500/mm3 and/or Platelets >20,000/mm3 without transfusions, and/or Hb >8.0 g/dL without transfusions.

  3. Change in adaptive behaviour [ Time Frame: up to 3 years (multiple visits) ]
    Measured using the Vineland Adaptive Behaviour scales against natural history of MPSIIIA

  4. Change in cognitive function [ Time Frame: up to 3 years (multiple visits) ]
    Measurement of cognitive score (standard scores, age equivalent scores and development quotient) using the Bayley Scales of Infant Development, 3rd Edition [BSID-III] or Kaufman Assessment Battery for Children, 2nd Edition [KABC-II] against natural history of MPSIIIA

  5. Change in patient behaviour [ Time Frame: up to 3 years ]
    Measured using the Sanfilippo Behaviour Rating Scale against natural history of MPSIIIA

  6. Change in patient quality of life [ Time Frame: Up to 3 years ]
    Measured using the Infant Toddler Quality of Life questionnaire against natural history of MPSIIIA

  7. Change in patient's daily living [ Time Frame: Up to 3 years ]
    Measured using the Children sleep Questionnaire against natural history data


Other Outcome Measures:
  1. To evaluate the effect of the IMP on heparan sulphate concentration in cerebrospinal fluid (CSF), plasma and urine [ Time Frame: 6 months and 12 months post-IMP treatments and multiple other visits over time ]
    Measure change in ng/ml glycosaminoglycans in CSF from baseline following IMP administration

  2. To evaluate the effect of the IMP on SGSH activity in CSF, plasma and peripheral blood mononuclear cells. [ Time Frame: 6 months and 12 months post-IMP treatments and multiple other visits over time ]
    Change in SGSH activity measured from baseline

  3. To evaluate clinical efficacy of the IMP on brain imaging biomarkers [ Time Frame: up to 3 years ]
    Measure change in brain volume (total brain, greey and white matter, ventricle volume) by MRI and compare to baseline and natural history data to help assess brain development

  4. To explore the presence of anti-SGSH antibodies following treatment with the IMP [ Time Frame: up to 3 years ]
    Measure whether an immune response is generated against the SGSH enzyme



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Months to 24 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent of a legally authorized guardian(s)
  2. Age at baseline ≥3 months and ≤24 months
  3. 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)
  4. 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
  5. 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.
  6. 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.

Exclusion Criteria:

  1. The subject has received stem cell, gene therapy or enzyme replacement therapy (any route of administration)
  2. Subject currently enrolled in other interventional clinical trials.
  3. Contraindications for MRI scans.
  4. The subject has a history of poorly controlled seizures.
  5. Homozygous or compound heterozygous for the S298P mutation or any other mutation known to be associated to slow-progressing phenotype.
  6. The subject is currently receiving psychotropic or other medications which, in the CI's opinion, would be likely to substantially confound test results.
  7. 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.
  8. Documented Human Immunodeficiency Virus (HIV) infection (positive HIV RNA and/or anti-p24 antibodies).
  9. 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.
  10. Myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia, or other serious haematological disorders.
  11. 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.
  12. Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing.
  13. Severe behavioural disturbances due to reasons other than MPS IIIA and likely to interfere with protocol compliance, as determined by the CI.
  14. Known sensitivity to busulfan.
  15. The receipt of live vaccinations within 30 days prior to study start.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04201405


Contacts
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Contact: MPSIIIA trial Manager 01613065882 mpsiiiatrial@manchester.ac.uk

Locations
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United Kingdom
Manchester University NHS Foundation Trust Recruiting
Manchester, United Kingdom, M13 9WL
Contact: Robert Wynn         
Contact: Simon Jones         
Sponsors and Collaborators
University of Manchester
Orchard Therapeutics
CTI Clinical Trial and Consulting Services
University College, London
Great Ormond Street Hospital for Children NHS Foundation Trust
Manchester University NHS Foundation Trust
Investigators
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Principal Investigator: Brian Bigger The University of Manchester
Principal Investigator: Robert Wynn MFT
Publications:

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Responsible Party: Rob Wynn, Professor, Manchester University NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT04201405    
Other Study ID Numbers: R119861
First Posted: December 17, 2019    Key Record Dates
Last Update Posted: February 20, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No, there is not a plan to make IPD available.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Mucopolysaccharidoses
Mucopolysaccharidosis III
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases