The lipid glucosylceramide (GlcCer) is present in all eukaryote cells. It is continuously synthesized from ceramide and UDP-glucose by the enzyme glucosylceramide synthase (GCS). GlcCer is metabolized in cells to the lipid lactosylceramide, the precursor of complex glycosphingolipids such as gangliosides and globosides. GlcCer is degraded in cells by the action of two β-glucosidases: lysosomal acid glucosylceramidase (glucocerebrosidase) named GBA1 and cytosolic glucosylceramidase named GBA2.
Gaucher disease (GD) is a recessively inherited disorder caused by deficient activity of lysosomal GBA1. Most GD patients develop a non-neuronopathic (type 1) course of disease and are treated by either enzyme replacement therapy (ERT – administration of recombinant GBA1) or substrate reduction therapy (SRT – treatment with inhibitors of GCS). The presently available therapeutic agents do not prevent neurological symptoms in patients suffering from neuronopathic GD (types 2/3) and there is thus an unmet medical need for these patients. Reduced activity of GBA1 has also been identified as major risk factor for development of Parkinson’s disease.
Potent GCS inhibitors are able to reduce GlcCer, the storage material in GD patients, and also higher glycosphingolipids including gangliosides and globosides, the causative storage materials in Tay-Sachs disease, GM1 gangliosidosis and Fabry disease. We earlier found a highly attractive lead GCS inhibitor, the iminosugar BiPheDNM. We next identified a series of analogues of this lead compound showing desired features such as potent inhibition of GCS and GBA2 but not of GBA1. Based on the promising findings with these compounds in cultured cells, we have planned to further develop selected agents towards a phase I/II clinical candidate.
For this, the present proof of concept project (Sphingolead – 693039) was conducted. The project Sphingolead aimed to yield a packet of relevant data and tools, as well as business case, to promote phase I/II clinical development of compounds together with a pharmaceutical partner.
The project has meanwhile been performed with great success. It has led to a partner, Azafaros, that will undertake clinical development of selected compound(s).
