gene therapy with modified autologous hematopoietic stem cells for patients with mucopolysaccharidosis type ii

Conditions: Mucopolysaccharidosis II

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.

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 the sugar glycosaminoglycans (gags), in particular, heparan sulphate (hs) and dermatan sulphate (ds). without this enzyme, these sugars accumulate in cells causing damage. 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 22 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. the therapy works by adding the gene therapy to cells taken from the child's body. the cells are then frozen and tested for safety before being given back to the child. to collect the cells, we will give the child some medicine to mobilize hematopoietic stem cells (hsc) from their bone marrow into the blood which can then be easily collected. a working copy of the ids gene is then placed into these cells in the laboratory (ex vivo). the modified hscs are then given back to the child via a blood infusion where they can travel to and live in the bone marrow. in the bone marrow compartment, these cells will produce new blood cells that can make the ids enzyme and can carry it around the whole body, including to the brain. this means the excess sugar chains can be broken down which may help cells to function normally. we think this will reduce mps ii symptoms and may help to prevent damage to the brain. to make sure the therapy is safe patients will be closely followed for 2 years within this trial. additional follow up for a minimum 15 years post therapy or as per current guidance will then be offered.

Eligibility criteria:
inclusion criteria: 1. written informed consent from a legally authorized guardian. 2. male, age at consent ≥3 months and ≤22 months. 3. 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. 4. 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. 5. 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. 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. 7. 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: 1. the patient has previously received stem cell or gene therapy 2. the patient has received modified intravenous ert or intra-thecal ert in a trial setting. 3. patient currently enrolled in another interventional clinical trial 4. the patient has a history of poorly controlled seizures 5. hemizygous for mutation known to be associated with non-neuropathic phenotype 6. the patient is currently receiving psychotropic or other medications which, in the ci's opinion, would be likely to substantially confound test results 7. 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 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. 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 10. myelodysplasia, cytogenetic alterations characteristic of myelodysplastic syndrome and acute myeloid leukaemia, or other serious haematological disorders 11. 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 12. visual or hearing impairment sufficient to preclude adequate neurodevelopmental testing 13. severe behavioural disturbances due to reasons other than mps ii 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 treatment start 16. known sensitivity to dmso