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

Overview

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.