Metachromatic Leukodystrophy

Overview of research to develop a treatment for MLD

Most researchers believe that MLD can be successfully treated by developing a method of getting arylsulfatase A into the lysosomes of the affected tissues, principally the central and peripheral nervous systems. Theoretically some patients may also be helped by drugs that block the synthesis of sulfatide (substrate reduction) or by drugs (chaperones) that stabilize ASA that contains a “mild “ mutation. These drugs have not been developed.

It also seems most likely that no treatment in the foreseeable future will be able to repair significant damage that has already occurred to the nervous system. This makes it imperative to diagnose an affected individual before the disease progresses. Newborn screening offers the best hope to achieve pre-symptomatic diagnosis. The following illustration of a cell is taken from an article in Wikipedia on lysosomes.

The gene for arylsulfatase A is on chromosome 22 in the chromatin within the nucleus of the cell. Messenger RNA for arylsulfatase A is made from the gene and travels to ribosomes on the rough endoplasmic reticulum. The mRNA sequence is translated into the protein sequence by the ribosome and the arylsulfatase A (ASA) protein enters the rough endoplasmic reticulum. At this point some sugars are added to the protein, other modifications are made and the protein is ready to be sent to the Golgi apparatus and then directed via specific signal to the lysosome.

Sulfatide is not identified in this illustration. It is present in the cell membrane in nervous tissue and the kidney. The cell membrane and other components of cells are constantly being renewed. Old structures that may be damaged are replaced with new structures. In this renewal process, old sulfatide is transported to lysosomes for degradation. The function of ASA in lysosomes is to start this degradative path. Individuals with MLD lack functional ASA and are unable to break down sulfatide. Sulfatide accumulates and ultimately results in cell death, tissue damage and metachromatic leukodystrophy.

How can ASA be put into lysosomes in patients with MLD?

There are two major challenges to delivering ASA to lysosomes in cells of the central and peripheral nervous systems. The first challenge is to get ASA through the blood brain barrier (BBB). The BBB protects the brain from harmful substances that may be present in blood but also provides a barrier to getting ASA from blood into the brain. The second challenge is to get ASA into the lysosomes of the neural cells.

There is no clinically acceptable solution to the BBB challenge but there is ongoing research. The second challenge is easier to solve. The successful treatments of non-neural tissues in other lysosomal storage diseases such as Gaucher disease (liver and spleen) uses the intravenous delivery of other lysosomal enzymes that have been engineered to be able to enter lysosomes.