Gene therapy for enzyme deficiency disease
MPS VI patients are deficient in arylsulfatase B (ARSB) activity. Symptoms include hydrocephalus, spinal cord compression, dwarfism/growth retardation, skeletal abnormalities and joint stiffness. Currently approved by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA), enzyme replacement therapy (ERT) has so far indicated limitations. A combination of limited efficacy as not all symptoms can be alleviated, the need for weekly therapy intravenously and high cost renders the treatment inaccessible to most patients. The 'Clinical trial of gene therapy for MPS VI - A severe lysosomal storage disorder' (MEUSIX) project is designing and running a multi-centre clinical trial to assess the safety of a gene therapy alternative. The treatment has the potential to provide a more effective, long-term solution to MPS VI: a single administration of adeno-associated viral (AAV) vectors targeting the liver can likely provide a lifelong source of ARSB. MEUSIX researchers have delivered well-established manufacturing processes and product-specific test methods to the selected manufacturers and research contractors. Work so far has developed and optimised the ARSB gene therapy vector production process in line with good manufacturing practice (GMP) (clinical-grade). Delays in manufacturing were compensated for by use of GMP-like material in non-clinical studies. Consequently, trials began on time according to the original project timeline as well as testing for toxicity, biodistribution and expression of the vector. Partners have established an independent Data and Drug Safety Monitoring Board to assess the progress, safety data and critical efficacy end points of the study. An appointed Ethics Advisory Group will oversee the development of guidelines on ethical aspects of patient treatment and care, and ensure uniformity of operations in all participating centres. The potential impact of expected deliverables from MEUSIX is that many of the limitations of ERT will be removed and a once-in-a-lifetime treatment will be available at a much reduced cost. Moreover, the enzyme will be available in all tissues affected by the disease as biodistribution will be on a wider basis. If proven safe and effective, the platform could be extended to other similar diseases such as haemophilia that require the sustained release of therapeutic proteins.
Keywords
Gene therapy, enzyme deficiency, MPS VI, ARSB, lysosomal storage
