Emerging therapeutic targets for Gaucher disease

Gaucher disease (GD) is an inherited metabolic disorder caused by mutations in the glucocerebrosidase (GBA1) gene. Although infusions of recombinant GBA ameliorate the systemic effects of GD, this therapy has no effect on the neurological manifestations. Patients with the neuronopathic forms of GD (nGD) are often severely disabled and die prematurely. The search for innovative drugs is thus urgent for the neuronopathic forms.

Here we briefly summarize the available treatments for GD. We then review recent studies of the molecular pathogenesis of GD, which suggest new avenues for therapeutic development.

Existing treatments for GD are designed to target the primary consequence of the inborn defects of sphingolipid metabolism, that is, lysosomal accumulation of glucosylceramide (GlcCer). Here we suggest that targeting other pathways, such as those that are activated as a consequence of GlcCer accumulation, may also have salutary clinical effects irrespective of whether excess substrate persists. These pathways include those implicated in neuroinflammation, and specifically, receptor-interacting protein kinase-3 (RIP3) and related components of this pathway, which appear to play a vital role in the pathogenesis of nGD. Once available, inhibitors to components of the RIP kinase pathway will hopefully offer new therapeutic opportunities in GD.