Metachromatic leukodystrophy or MLD is a lysosome overload disease primarily affecting the central nervous system. These diseases constitute a family of genetic diseases caused by missing or defective enzymes. Many of the symptoms of some of these conditions can be effectively treated by intravenous administration of synthetic enzymes. These enzymes are relatively large in size to be able to pass from the bloodstream to the central nervous system when given intravenously. Therefore, it is unlikely that they can act on central nervous system disorders associated with some forms of lysosome overload disease including MLD. The Shire Laboratory has designed a clinical research program to study the direct delivery of synthetic human arylsulfatase, or rhASA, into the central nervous system to overcome its deficiency. This clinical trial for MLD is in a early phase of development.

In animal models, the enzyme rhASA has been detected in all areas of the brain. The administered enzyme is deposited in the lysosomes of oligodendrocytes, the myelin cells of the brain where sulfatides accumulate abnormally during the disease.

Weekly administration of rhASA intrathecally (i.e. by direct injection into the area surrounding the spinal cord) in another animal model of MLD has been shown to decrease sulfatides in the central nervous system, as well as in the spinal cord (near the injection site) and in the deep tissues of the brain. These series of experiments demonstrate that the administration of rhASA by the intrathecal route can reach the target tissues of the central nervous system.

The data from these studies is useful for further research in humans. However, results observed in animals do not automatically correlate with what is observed in humans.

The Shire Laboratory is currently conducting a clinical trial to assess the safety of a synthetic form of ASA in MLD patients. This study, in addition to safety, will assess possible changes in coarse and fine motor skills, swallowing, cognition, adaptive behavior and the peripheral nervous system. This study is planning an extension phase that will assess longer term safety and clinical effect. The Shire laboratory is also studying the natural history of the disease in order to better understand its course in sick children and adults.