- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05665166
Autologous Ex-vivo Gene Modified HSCT in MPSII
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)
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.
Study Overview
Status
Conditions
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Contact
- Name: Laura Booth
- Phone Number: 0161 2755112
- Email: mpsiitrial@manchester.ac.uk
Study Contact Backup
- Name: Robert Wynn, Prof
- Phone Number: 0161 2755112
- Email: robert.wynn@mft.nhs.uk
Study Locations
-
-
-
Manchester, United Kingdom
- Recruiting
- Manchester University Foundation Trust
-
Contact:
- Robert Wynn
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- 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
|
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
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To evaluate the tolerability of the IMP in MPS II patients
Time Frame: Up to 24 months post IMP
|
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
Time Frame: Up to 24 months post IMP
|
Presence of replication competent virus and integration events in the leukocytes
|
Up to 24 months post IMP
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Heparan sulphate in cerebrospinal fluid (CSF)
Time Frame: baseline, 3, 6, 12, and 24 months post-IMP
|
baseline, 3, 6, 12, and 24 months post-IMP
|
Heparan sulphate in plasma
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Heparan sulphate in urine
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Glycosaminoglycan (GAG) ratio in urine by dimethylmethylene blue [DMB]
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
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
Time Frame: Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
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
Time Frame: Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
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
Time Frame: Baseline, 3, 6, 12, and 24 months post-IMP
|
Baseline, 3, 6, 12, and 24 months post-IMP
|
VCN in total leucocyte and the bone marrow
Time Frame: baseline and 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
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)
Time Frame: baseline, 1, 6, 12 and 24 month's post-IMP
|
baseline, 1, 6, 12 and 24 month's post-IMP
|
IDS enzyme activity in the bone marrow within or above normal range
Time Frame: 12 months and at multiple other visits over time
|
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)
Time Frame: baseline, 6, 12, 18 and 24 months post- IMP treatment
|
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)
Time Frame: baseline, 6, 12, 18 and 24 months post-IMP treatment
|
baseline, 6, 12, 18 and 24 months post-IMP treatment
|
Other Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Dermatan sulphate in cerebrospinal fluid (CSF)
Time Frame: Baseline, 3, 6, 12, and 24 months post-IMP
|
Baseline, 3, 6, 12, and 24 months post-IMP
|
Dermatan sulphate in plasma
Time Frame: Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Dermatan sulphate in urine
Time Frame: Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
IDS enzyme activity in subpopulations (i.e., CD3+, CD15+, CD19+ cells) measured using IDS enzyme activity assay
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
VCN in blood subpopulations (CD3+, CD15+, CD19+ cells) measured using RT-qPCR
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Obstructive sleep apnoea assessed by polysomnography (using the apnoea-hypopnoea index [AHI])
Time Frame: baseline, 6, 12 and 24 months post-IMP
|
baseline, 6, 12 and 24 months post-IMP
|
Presence and persistence of anti-IDS antibodies in blood and CSF
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Hearing measured using tympanometry and distortion product optoacoustic emission testing
Time Frame: baseline, 12 and 24 months post-IMP
|
baseline, 12 and 24 months post-IMP
|
Height measured by standard calibrated stadiometer from the age they can stand independently, prior to this measuring length
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post- IMP
|
baseline, 1, 3, 6, 9, 12, 18 and 24 months post- IMP
|
Presence of exploratory biomarkers
Time Frame: baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
baseline, 1, 3, 6, 9, 12, 18 and 24 months post-IMP
|
Cognitive score (GSV) measured using the Bayley Scales of Infant Development, 3rd Edition (BSID-III) or Kaufman Assessment Battery for Children, 2nd Edition (KABC-II)
Time Frame: baseline and 6, 12, 18 and 24 months post-IMP
|
baseline and 6, 12, 18 and 24 months post-IMP
|
Adaptive behaviour (GSV) measured using the Vineland Adaptive Behaviour Scales, 3rd Edition (VABS-III)
Time Frame: baseline and 6, 12, 18 and 24 months post-IMP
|
baseline and 6, 12, 18 and 24 months post-IMP
|
Rate of fidelity analysis of neurocognitive assessments looking at the quality of interactions
Time Frame: baseline, 6, 12, 18 and 24 months post-IMP treatment
|
baseline, 6, 12, 18 and 24 months post-IMP treatment
|
Parental reported observations of child's development by using collated comments in qualitative descriptive analyses
Time Frame: baseline, 6, 12, 18 and 24 months post-IMP treatment
|
baseline, 6, 12, 18 and 24 months post-IMP treatment
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Robert Wynn, Manchester Foundation Trust
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Metabolic Diseases
- Nervous System Diseases
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- Connective Tissue Diseases
- Carbohydrate Metabolism, Inborn Errors
- Metabolism, Inborn Errors
- Lysosomal Storage Diseases
- Mucinoses
- Mental Retardation, X-Linked
- Intellectual Disability
- Heredodegenerative Disorders, Nervous System
- Mucopolysaccharidosis II
- Mucopolysaccharidoses
Other Study ID Numbers
- R125432
- 2021-000400-38 (EudraCT Number)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Mucopolysaccharidosis II
-
University of ChicagoNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National... and other collaboratorsCompletedKrabbe Disease | Mucopolysaccharidosis Type II (MPS II) | Mucopolysaccharidosis Type I (MPS I) | Mucopolysaccharidosis Type III (MPS III) | Mucopolysaccharidosis Type VI (MPS VI)United States
-
University of MinnesotaNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National... and other collaboratorsCompletedMucopolysaccharidosis Type I | Mucopolysaccharidosis Type II | Mucopolysaccharidosis Type VI | Mucopolysaccharidosis Type IV | Mucopolysaccharidosis Type VIIUnited States, Canada
-
REGENXBIO Inc.Active, not recruitingMucopolysaccharidosis Type II (MPS II)United States, Brazil
-
REGENXBIO Inc.Active, not recruitingMucopolysaccharidosis Type II (MPS II)United States, Canada
-
Lundquist Institute for Biomedical Innovation at...CompletedMucopolysaccharidosis Type I | Mucopolysaccharidosis Type II | Mucopolysaccharidosis Type VIUnited States
-
University Hospital HeidelbergCompletedMucopolysaccharidosis Type I | Mucopolysaccharidosis Type II | Coping Behavior | Mucopolysaccharidosis Type III | Behavior DisordersGermany
-
TakedaCompletedMucopolysaccharidosis (MPS)Brazil
-
JCR Pharmaceuticals Co., Ltd.Active, not recruitingMucopolysaccharidosis IIJapan
-
JCR Pharmaceuticals Co., Ltd.Completed
-
AO GENERIUMRecruitingMetabolic Diseases | Mucopolysaccharidosis Type IIRussian Federation
Clinical Trials on Autologous CD34+ HSCs transduced ex vivo with CD11B LV encoding human IDS tagged with ApoEII
-
University of California, Los AngelesRecruitingAdenosine Deaminase Severe Combined Immune DeficiencyUnited States
-
CSL BehringTerminated
-
bluebird bioRecruitingSickle Cell DiseaseUnited States
-
bluebird bioCompletedSickle Cell DiseaseUnited States