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You are here: Home Research Group Gieselmann Group Matzner Research


Research of Group Matzner


Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is caused by a functional deficiency of arylsulfatase A (ASA). ASA catalyzes the degradation of sulfatide, an acidic sphingolipid which is present in myelin sheaths. Lack of ASA causes progressive intralysosomal accumulation of sulfatide in oligodendrocytes and Schwann cells, ultimatelly leading to demyelination of the PNS and CNS. MLD patients typically develop first clinical signs at the age of 2 years and show rapidly deteriorating neurological symptoms causing death before age 9. There is no therapeutic option which can halt or retard the disease progression.

We are interested in therapy approaches for MLD. The N-glycans of ASA harbour mannose 6-phosphate (M6P) residues which bind to M6P-receptors of the plasma membrane mediating endocytosis and lysosomal delivery of the ligand. M6P-dependent endocytosis therefore opens the possibility to treat MLD by substitution therapy. Using ASA knockout mice as an animal model of MLD, we are testing and optimizing different routes of enzyme delivery (in vivo gene therapy, ex vivo gene therapy, cell therapy, enzyme replacement therapy). For enzyme replacement therapy (ERT) recombinantly expressed ASA is supplied by repeated intravenous injection. Treatment reduces sulfatide storage throughout the nervous system and has a favourable benefit-to-risk ratio leading to the approval of a clinical phase I/II trial.

Attempts to optimize ERT focus on the blood-brain barrier which hampers the transfer of therapeutic enzyme from the circulation to the brain parenchyma. To overcome the BBB more efficiently we are exploiting peptides which are actively transcytosed across the BBB. Fusion proteins between ASA and such BBB-shuttle peptides are tested in vitro using a porcine cell culture model of the BBB and in vivo using an in situ mouse brain perfusion model.

Our second focus of interest is on the pathomechanisms underlying MLD. Progressive microgliosis seems to play a pivotal role in the CNS pathogenesis. According to our working hypothesis, activated microglial cells secrete proinflammatory cytokines promoting metabolic stress and apoptosis of oligodendrocytes. Phagocytosis of the cellular breakdown products by microglial cells in turn amplifies their activation state and cytokine release. This vicious cycle may cause a progressive chronic inflammation of the CNS triggering the widespread and devastating demyelination observed in the final stages of MLD. To identify new therapeutic targets, we are analysing microglial activation markers, cytokines and cytokine receptors expressed in the CNS of MLD-mice. Therapies with steroidal or non-steroidal anti-inflammatory drugs may represent an alternative to substitution therapy.

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