New Approach for the Treatment of Gauchers Disease


Return to contents page


An exciting new discovery has led two researchers at the Glycobiology Institute, University of Oxford, to investigate the possibility of an alternative treatment for Gauchers Disease, which may also help other lysosomal storage diseases. Still in its very early stages, Dr Frances Platt and Dr Terry Butters, explain how it works:

For the past few years we have been studying the activities of a substance called NB-DNJ, trying to understand why it inhibits the replication of certain viruses. This agent is similar to many naturally occurring compounds found in plants and micro-organisms, and is similar to glucose. It has been administered to patients with chronic viral infections and appears to be generally well tolerated.

New Activity of the Drug, NB-DNJ

In the course of our experiments, we made the unexpected observation that NB-DNJ inhibits an important cellular enzyme. The enzyme in question is responsible for the first step in the formation of glycolipids (fatty molecules modified by the addition of sugars), which involves the attachment of glucose to the lipid.

The practical consequence of inhibiting this enzyme is that we can control the amount of glycolipid made by the cell. This offers the potential for treating some of the lysosomal storage diseases, such as Gauchers disease and Tay-Sachs disease, in which the storage materials contains the same glycolipid backbone.

Glycolipid Storage Diseases

These disorders result from the inheritance of defects in the genes which code for enzymes which are needed to break down glycolipids in lysosomes (specialised places in the cell where unwanted molecules are degraded).

The non-degraded glycolipids accumulate over time in the lysosomes and result in a number of different symptoms, depending on the type of glycolipid which the individual cannot degrade. Members of the Association will know that Gauchers disease is one of the glycolipid storage disorders.

Treatment Strategies

There are three main strategies for treating these diseases. The first is enzyme replacement therapy in which the patient is infused with fully active enzyme. This has proved to be a very successful approach for the treatment of Type 1 Gauchers disease but does not appear to be the whole answer for Type 2 and Type 3 Gauchers disease.

The second is gene therapy, which aims to introduce a copy of the normal gene into the patient which will lead to the production of the normal enzyme and correct the enzyme deficiency.

The third possible strategy is not based on correcting the defect but modifying what the cell manufactures to compensate for the defective enzyme. To understand the basis for this approach we need to consider some of the events which normally occur in the body's cells.

All the cells in our tissues actively manufacture new molecules and degrade molecules that they no longer require. Normally these two processes (synthesis and degradation) are balanced so that we do not develop deficiencies or build up excessive quantities of molecules within the cell.

In the glycolipid lysosomal storage diseases, the defective enzyme cannot cope with all the molecules the cell needs to degrade, because their formation and turn-over carries on in an unregulated manner.

The substrate deprivation strategy which we are developing aims to reduce the amount of glycolipid that is formed so that even a partially active enzyme can totally degrade all the molecules entering the lysosome. To be successful this strategy requires a specific inhibitor of glycolipid synthesis, such as the drug NB-DNJ.

NB-DNJ and the Prevention of Lysosomal Storage

Over the last two years we have been investigating the therapeutic potential of NB-DNJ in three separate ways.

The first approach was to imitate Gauchers disease in mouse macrophages to see if we could prevent the storage of glucocerebrosidase in the lysosomes by treatment with NB-DNJ.

We found that this worked very well and no lysosomal storage occurred in NB-DNJ-treated mouse Gaucher cells - at least in the test-tube.

We are now studying cells derived from patients suffering from Gauchers disease and Tay-Sachs disease (kindly provided by Dr Bryan Winchester, Institute of Child Health, London) to see if we can prevent accumulation of glycolipids with NB-DNJ treatment, and to see if NB-DNJ treated cells can degrade the material which has already been stored within the lysosome. These studies are currently in progress, and the preliminary results look promising.

The third approach involves treating mice which develop Tay-Sachs disease (kindly provided by Dr Richard Proia, NIH, USA) to see if NB-DNJ can prevent the disease from occurring.

If we can prevent lysosomal storage in this mouse model of Tay-Sachs disease, and in other related lysosomal diseases, it will provide important information for the treatment of human patients suffering from these severe categories of lysosomal disease.

Identification of a Second Drug

We have recently identified a second, more selective drug called NB-DGJ (which is very similar to NB-DNJ). NB-DGJ may also be useful in treating glycolipid lysosomal storage diseases.

Unlike NB-DNJ, which has been administered to humans in clinical trials as a potential anti-viral compound, NB-DGJ has yet to be evaluated for safety in animals. Experiments are currently underway to try and find out whether this second drug has any advantages over NB-DNJ.

The Future

We believe that these drugs have the potential to be of benefit in the treatment of some of the severe glycolipid storage diseases that are otherwise unresponsive to therapy.

We are currently discussing with Prof Tim Cox (Addenbrooke's Hospital, Cambridge) the possible strategies for evaluating NB-DNJ in the human setting within the next few years.


Recent report on OGT 918 (July 1999).

A New Drug on Trial for Gaucher's Disease ( January 1999).

Return to New Treatments

Return to contents page

Source: Gauchers News March 1996. Updated January 1999.

© Copyright Gauchers Association 1996