Autologous Ex-vivo Gene Modified HSCT in MPSII

Study Overview
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Brief Summary
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Patients with MPS II have a clinical disorder marked by progressive brain disease, neurological and somatic 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 IDS gene) in MPSII patients. Following treatment with the gene therapy patients will be followed up for a minimum of 2 years.

Detailed Description
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Mucopolysaccharidosis type II (MPSII, Hunter Syndrome) is a rare paediatric X-linked lysosomal storage disease caused by a deficiency in iduronate-2-sulphatase (IDS), due to a mutation on the IDS gene. IDS is essential for the breakdown of glycosaminoglycans (GAGs), in particular, heparan sulphate (HS) and dermatan sulphate (DS). Currently, enzyme replacement therapy (ERT) is the only clinically approved treatment available for MPSII. However, ERT is a supportive therapy and is intended to alleviate symptoms and improve patient quality of life, rather than addressing the pathogenic mechanisms of the disease. To date, there is no effective disease-modifying treatment. This study aims to recruit 5 patients with MPS II who satisfy the inclusion and exclusion criteria and provide full consent, between 3 months and 12 months of age at screening. 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 IDS gene tagged with ApoEII. Patients will be followed up for a minimum of 2 years after gene therapy.

Official Title
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A Phase I/II, Study of Autologous CD34+ Haematopoietic Stem Cells Transduced ex Vivo With CD11B Lentiviral Vector Encoding Human IDS Tagged With ApoEII in Patients With Neuronopathic Mucopolysaccharidosis Type II (nMPS II, Hunters Syndrome)

Conditions
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Mucopolysaccharidosis II

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from a legally authorized guardian. Male, age at consent ≥3 months and ≤12 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. Exclusion Criteria: 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 Known sensitivity to DMSO

Ages Eligible for Study
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Minimum Age: 3 Months
Maximum Age: 12 Months

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase I-II prospective, single-centre, non-randomised, open label, safety and proof of concept study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous CD34+ HSCs transduced ex vivo with CD11B LV encoding human IDS tagged with ApoEII<br> | Genetic: Autologous CD34+ HSCs transduced ex vivo with CD11B LV encoding human IDS tagged with ApoEII<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heparan sulphate in cerebrospinal fluid (CSF) |  | baseline, 3, 6, 12, and 24 months post-IMP | 
| Heparan sulphate in plasma |  | baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP | 
| Heparan sulphate in urine |  | baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP | 
| Glycosaminoglycan (GAG) ratio in urine by dimethylmethylene blue [DMB] |  | baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP | 
| IDS enzyme activity in plasma within or above normal range measured using an IDS enzyme activity assay |  | Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP | 
| IDS enzyme activity in total leucocytes within or above normal range measured using an IDS enzyme activity assay |  | Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP | 
| IDS enzyme activity in CSF within or above normal range measured using an IDS enzyme activity assay |  | Baseline, 3, 6, 12, and 24 months post-IMP | 
| VCN in total leucocyte and the bone marrow |  | baseline and 1, 3, 6, 9, 12, 18 and 24 months post-IMP | 
| Proportion of cells containing the inserted IDS.ApoEII gene in total bone marrow colony forming units (CFUs) |  | baseline, 1, 6, 12 and 24 month's post-IMP | 
| IDS enzyme activity in the bone marrow within or above normal range |  | 12 months and at multiple other visits over time | 
| Cognitive scores (standard scores, age-equivalent scores and development quotient) measured using the Bayley Scales of Infant Development, 3rd Edition (BSID-III) or Kaufman Assessment Battery for Children, 2nd Edition (KABC-II) |  | baseline, 6, 12, 18 and 24 months post- IMP treatment | 
| Adaptive behaviour (age-equivalent scores) measured using the Vineland Adaptive Behaviour Scales, 3rd Edition (VABS-III) |  | baseline, 6, 12, 18 and 24 months post-IMP treatment |