Therapeutic Targeting of Lysosomal Enzyme Glycoforms in Hunter Syndrome and Fabry Disease
3 year project supported by Jeans for Genes £231,635
There are two lysomal storage disorders caused by genetic defects in one of the sex chromosomes: Hunter syndrome and Fabry disease. Differences between these two conditions in disease severity in females lie at the core of this proposal, which offers therapeutic benefit in several Lysomal Storage Disorders. If we were able to determine why women harbouring one copy of a defective gene for Hunter Syndrome almost never develop the condition, whereas women carrying a single Fabry disease gene nearly always suffer from this disorder, we would be in a position greatly to enhance the action of treatments already available for patients with many lysosomal diseases.

Enzyme replacement therapy depends on the ability of cells to take up enzyme from the surrounding fluid and target it to the lysosome, where it has its biological effect. Cells producing adequate amounts of enzyme usually export a proportion into the surrounding fluid. Every normal female is a mosaic; in some of her tissues maternal genes are active, whilst in others, paternal genes are active. Thus females with sex-linked conditions are made up of patches of tissue with normal production of enzyme and patches with an impaired production. In Fabry disease and Hunter syndrome, females carrying the defective gene usually have detectable enzyme in body fluids. In Hunter syndrome, this enzyme apears to be taken up by the defective cells thus preventing expression of the disease, through a 'natural' enzyme replacement therapy. This process does not appear to work in Fabry disease, permitting the accumulation of storage materials in affected tissues with resulting features of disease in most females. This is all the more intriguing given that the pharamaceutical enzyme, supposedly similar in structure to the natural enzyme, clears storage and provides clinical benefit to female patients.

This research project will examine aspects of the structure and the distribution of the relevant enzyme in Fabry Disease and Hunter Syndrome. We will examine the question whether the natural Fabry enzyme is modified in the circulation in a way that prevents its uptake into deficient cells. The uptake of the natural, therapeutic and artificially modified enzyme in diverse relevant cell types will be explored. On the basis of this research whether the structure of the enzyme can be optimied to permit uptake of the natural enzyme in females with Fabry disease and permit the development of enzyme treatments that are more effectively targetted to diseased tissue in a broad range of lysomal storage diseases.