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

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Mucopolysaccharidosis Type IIIA
• Intervention / Treatment: Drug: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene

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.

• Study Type: Interventional
• Enrollment (Estimated): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Manchester University NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 2 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

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: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate overall survival	Overall survival at 36 months post IMP administration compared to natural history data	up to 3 years
To evaluate peripheral engraftment of the IMP	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.	within 42 days of treatments
Change in adaptive behaviour	Measured using the Vineland Adaptive Behaviour scales against natural history of MPSIIIA	up to 3 years (multiple visits)
Change in cognitive function	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	up to 3 years (multiple visits)
Change in patient behaviour	Measured using the Sanfilippo Behaviour Rating Scale against natural history of MPSIIIA	up to 3 years
Change in patient quality of life	Measured using the Infant Toddler Quality of Life questionnaire against natural history of MPSIIIA	Up to 3 years
Change in patient's daily living	Measured using the Children sleep Questionnaire against natural history data	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the effect of the IMP on heparan sulphate concentration in cerebrospinal fluid (CSF), plasma and urine	Measure change in ng/ml glycosaminoglycans in CSF from baseline following IMP administration	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.	Change in SGSH activity measured from baseline	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	Measure change in brain volume (total brain, grey and white matter, ventricle volume) by MRI and compare to baseline and natural history data to help assess brain development	up to 3 years
To explore the presence of anti-SGSH antibodies following treatment with the IMP	Measure whether an immune response is generated against the SGSH enzyme	up to 3 years

Collaborators and Investigators

• Sponsor: University of Manchester
• Collaborators: University College, London; Manchester University NHS Foundation Trust; Orchard Therapeutics; Great Ormond Street Hospital for Children NHS Foundation Trust; CTI Clinical Trial and Consulting Services
• Investigators: Principal Investigator: Brian Bigger, The University of Manchester; Principal Investigator: Robert Wynn, MFT

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2020
• Primary Completion (Estimated): October 30, 2024
• Study Completion (Estimated): October 30, 2024

Study Registration Dates

• First Submitted: December 5, 2019
• First Submitted That Met QC Criteria: December 16, 2019
• First Posted (Actual): December 17, 2019

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Mucopolysaccharidosis III
• Other Study ID Numbers: R119861

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No, there is not a plan to make IPD available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No