Glycosphingolipid antigen depletion as a novel strategy for treating autoimmune peripheral nerve diseases.

We are interested in human paralytic diseases that are caused by the bodies immune system attacking peripheral nerves through a mistake in immunological programming. One way to treat patients would be to reduce the levels of the molecules on nerve cells that the immune system recognises. We have shown in cells grown in culture in the laboratory that this approach works. We now aim to find out whether similar benefit can be achieved in a living mouse with this type of disease. If this is successful, which we expect it to be, this will pave the way for testing this approach in patients affected by these paralytic nerve disorders. One advantage to our plan is that the drugs we intend to use are already available for use in patients with other diseases, but have never been tried in autoimmune nerve paralysis. Before this can be done, they must be thoroughly tested in an animal model of the disease.

Guillain-Barre syndromes (GBS) and their chronic counterparts are leading causes of neuromuscular paralysis, affecting 1 in a 1000 individuals worldwide at some point in their lives, and leaving 20% disabled or dead. Current therapies comprise primitive, non-specific immunotherapies that are only partially effective. In many cases, an acute or chronic antibody response to infectious agents inadvertently attacks identical sugar epitopes on gangliosides on the surface of peripheral nerves, leading to severe nerve damage. Willison has modelled anti-ganglioside antibody-mediated forms of autoimmune neuropathy in the mouse, focusing on the distal motor nerve as a model site for observing injury and proven the central role for gangliosides in targeting antibodies to the nerve that is dependent upon the membrane concentration of gangliosides. Therefore, by reducing neural ganglioside levels using the biosynthetic inhibitor drug miglustat, (approved for Gaucher disease and pioneered by Platt), we may deplete the antigenic target below the critical threshold level at which anti-ganglioside antibodies significantly bind, thereby attenuating nerve injury. We have proof of principle in vitro (and a patent filing) demonstrating the efficacy of miglustat in protecting a nerve cell line from antibody-mediated injury. We therefore propose a collaborative project (Platt/Willison) to model this paradigm in the GBS mouse. Nerve ganglioside levels in treated mice will be measured and the pathogenic action of anti-ganglioside antibodies on mouse nerves assessed. Success in these studies would lead to clinical trials in man, initially in chronic forms and recovery phases of anti-ganglioside antibody-mediated neuropathy in which antibodies are persistently present.