14800-DvRappard

38 Chapter 2 Enzyme replacement therapy herationaleforenzymereplacementtherapy(ERT)isthatextracellularlysosomalenzymes are taken up by cells and transported by endocytic receptors to the lysosome where they become active. 35 Traditionally, ERT is done by intravenous injection of an enzyme and has shown to be effective for several lysosomal disorders without involvement of the CNS such as Gaucher disease type 1, Fabry disease, mucopolysaccharidosis type I, II and VI and Pompe disease. 35 Animal studies The concept of enzyme replacement therapy has been proven to be effective in improving the function of the nervous system in several preclinical studies. An ASA deficient knock out mouse model has been generated, which indeed accumulated sulfatides. However, these mice did not develop demyelination, which was thought to be due to an insufficient buildup of sulfatides. 6 Transgenic mice were generated and crossed with ASA deficient mice resulting in an aggravated disease phenotype. In these mice, sulfatides were increased about two to threefold and demyelination in both peripheral and central nervous system was seen. 8 Matzner et al 36 were the first to provide proof of principle of enzyme replacement therapy when they reported a decline of sulfatide storage in kidney and peripheral nerves following intravenous injection of rhASA in ASA knockout mice. Furthermore, a reduction of storage in the central nervous systemwas noted, which could not clearly be explained since the brain did not acquire enzyme levels of more than 0.1% of wild type levels due to the impermeability of the blood brain barrier. Stroobants et al 35 reported a preclinical experiment in which the blood brain barrier of mice was bypassed by continuous infusion of rhASA into the brain ventricles using miniature osmotic pumps. They found an improvement in nervous system function and reported no adverse immunological effects. Furthermore, a reduction in sulfatide storage in the brain and spinal cord of mice was observed following intrathecal ERT. 6 This suggests that rhASA is able to cross brain capillaries in a cell culture model of the blood brain barrier. The hydrolyzation of the storage material, however, seemed to be inversely dependent on the amount of accumulated sulfatides. Clinical studies In MLD, ERT has been administered intravenously but was found not to be effective, due to the inability of the enzyme to cross the blood brain barrier and thereby the inability to reach the nervous tissue (unpublished data). Different routes of administration, such as intracerebral agent delivery, are currently being tested in clinical trials to overcome