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

NCT05665166 | Active Not Recruiting Phase 1

• 2 other identifiers: R1254322021-000400-38
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

MPS II is a genetic disorder that affects boys. Boys with MPS II are missing a working enzyme known as iduronate-2-sulfatase (IDS) which is needed to break down long sugar chains in the body. When this enzyme is missing, these sugars build up to excess causing damage, and stop organs such as the brain from working properly. Children with MPS II often have progressive symptoms such as developmental delay and physical problems. The only approved treatment for MPS II is enzyme replacement therapy. This involves a regular infusion of the missing enzyme into the blood stream. But this treatment only helps some symptoms and cannot help problems in the brain. This study will be the first in human clinical trial to check whether using a gene therapy in children with MPS II is safe and is able to provide enough enzyme to help with disease symptoms. Gene therapy involves changing the genetic information that makes up a person, by taking a correct version of the gene that is needed to make the working IDS enzyme and putting it back into the body. This means that the body can then make the missing enzyme itself. The good thing with this therapy is that the body should be able to make this enzyme forever. To make sure the therapy is safe and working patients will be closely followed for 2 years.

Conditions

Mucopolysaccharidosis II

Outcome Measures

Primary Outcomes (2)

• To evaluate the tolerability of the IMP in MPS II patients

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

  Up to 24 months post-IMP delivery

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

  Presence of replication competent virus and integration events in the leukocytes

  Up to 24 months post-IMP delivery

Secondary Outcomes (13)

• IDS enzyme activity in total leukocytes

  Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP delivery

• Heparan sulphate in plasma

  baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP delivery

• Heparan sulphate in urine

  baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP delivery

• Glycosaminoglycan (GAG) ratio in urine

  baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP delivery

• IDS enzyme activity in plasma

  Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP delivery

Other Outcomes (15)

• Dermatan sulphate in cerebrospinal fluid (CSF)

  Baseline, 3, 6, 12, and 24 months post-IMP delivery

• Dermatan sulphate in plasma

  Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP delivery

• Dermatan sulphate in urine

  Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP delivery

Study Arms (1)

Autologous CD34+ HSCs transduced ex vivo with CD11B LV encoding human IDS tagged with ApoEII

EXPERIMENTAL

Genetic: Autologous CD34+ HSCs transduced ex vivo with CD11B LV encoding human IDS tagged with ApoEII

Interventions

Autologous CD34+ HSCs transduced ex vivo with CD11B LV encoding human IDS tagged with ApoEII GENETIC

Autologous CD34+ haematopoietic stem cells from MPS II patients will be genetically modified ex vivo using CD11b.IDS-ApoEII Lentiviral Vector (LV), a self-inactivating (SIN) LV expressing the human codon-optimized IDS gene tagged with ApoEII and regulated by a human CD11b myeloid-specific promoter. These transduced CD34+ HSCs will then be cryopreserved until the time of infusion back to the patients

Autologous CD34+ HSCs transduced ex vivo with CD11B LV encoding human IDS tagged with ApoEII

Eligibility Criteria

• Age: 3 Months - 22 Months
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Written informed consent from a legally authorized guardian.
• Male, age at consent ≥3 months and ≤22 months.
• Normal cognitive function or mild cognitive dysfunction (patient has a Development Quotient (DQ) score ≥70 at screening as determined by the Bayley Scale of Infant Development-third edition (BSID-III), cognitive domain), or assessed as normal or only mildly impaired by experienced neuropsychologist.
• Close male relative with known severe (progressive neuronopathic) phenotype of MPSII, or genotype associated with progressive neuronopathic phenotype. This is to be confirmed by the independent expert reviewers.
• IDS activity ≤10% of the Lower Limit of Normal as measured in leucocytes or plasma, plus either (1) a normal enzyme activity level of at least one other sulfatase (to rule out multiple sulfatase deficiency) as measured in leucocytes, or (2) a documented mutation in the IDS 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.
• Patients and their parents/legal guardians must be willing and able to comply with study restrictions and to commit to attend clinic for the required duration during the study and follow-up period as specified in the protocol.

You may not qualify if:

• The patient has previously received stem cell or gene therapy
• The patient has received modified intravenous ERT or intra-thecal ERT in a trial setting.
• Patient currently enrolled in another interventional clinical trial
• The patient has a history of poorly controlled seizures
• Hemizygous for mutation known to be associated with non-neuropathic phenotype
• The patient is currently receiving psychotropic or other medications which, in the CI's opinion, would be likely to substantially confound test results
• The patient 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. Patients 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 patient has a medical condition or extenuating circumstance that, in the opinion of the CI, might compromise the patient's ability to comply with protocol requirements, the patient's well-being or safety, or the interpretability of the patient's clinical data
• Visual or hearing impairment sufficient to preclude adequate neurodevelopmental testing
• Severe behavioural disturbances due to reasons other than MPS II 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 treatment start

Sponsors & Collaborators

• University of Manchester: lead
• LifeArc: collaborator
• CTI Clinical Trial and Consulting Services: collaborator
• Great Ormond Street Hospital for Children NHS Foundation Trust: collaborator
• Manchester University NHS Foundation Trust: collaborator

Study Sites (1)

Manchester University Foundation Trust

Manchester, United Kingdom

Location

MeSH Terms

Conditions

Mucopolysaccharidosis II

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Robert Wynn

  Manchester Foundation Trust

  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: SPONSOR

Model Details: Phase I-II prospective, single-centre, non-randomised, open label, safety and proof of concept study

Study Record Dates

• First Submitted: December 7, 2022
• First Posted: December 27, 2022
• Study Start: June 1, 2023
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2028
• Last Updated: March 27, 2026

Record last verified: 2026-03

Locations

GB (1)