Cisterna magna delivery of therapeutic lysosomal enzyme to correct CNS pathology in lysosomal storage disorders

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Lysosomal storage disorders (LSD) are inherited diseases that affect about 1 in 7700 Australian children; all share common physical symptoms include heart and breathing difficulties, stiff joints, skeletal deformities, enlarged head, and a characteristic facial appearance. Two-thirds of patients will also develop brain disease. The lysosome is a component of each cell in the human body; its role it is to break down and remove waste from the cell. This involves a series of proteins (enzymes) that act in sequence. A LSD arises when the lysosome lacks the activity of one protein in this chain. The loss of protein activity impairs the waste removal process. Waste begins to 'store', clogging the cell and interfering with its usual functions. This gives rise to devastating symptoms that worsen over time as storage increases. Brain disease in LSD has profound effects on the child: mental capacity declines, they become hyperactive and aggressive and progressively lose learned skills (e.g. walking, talking) and ability to control bodily functions. Artifically made protein is being successfully used to treat some LSD via intravenous injection. However, it is not able to access the brain because of a protective barrier that surrounds it. This project tests a method to deliver protein to the brain to reduce and stop waste build-up. It involves the injection of artificially made protein into the fluid surrounding the brain and spinal cord using techniques being used to treat other diseases. This method is likely to be the quickest way in which we can treat both the body AND the brain of an affected child. We have diagnosed animal models who were born with a LSD with brain disease, called MPS IIIA. Their symptoms are similar to that seen in humans over the course of the disease, making them ideal for study in this project. Success in this project will allow us to advance this treatment to human trials.