Emerging therapeutic targets for Gaucher disease

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Keywords:

• cell death
• Gaucher disease
• glucocerebrosidase 1
• glucocerebrosidase 2
• necroptosis
• neuroinflammation
• pathogenesis
• RIP3

Acknowledgment

We thank Rotem Tidhar for help with the figures.

Declaration of interest

Research into Gaucher disease in the Futerman laboratory is supported by the Children’s Gaucher Research Fund and the Minerva Foundation. AH Futerman is the Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science. Research into Gaucher disease in the Cox laboratory is currently supported by the Medical Research Council UK (Stratified Medicine Programme RCAG/499) and the National Institute for Health Research, Comprehensive Biomedical Research Centre (RCAG/428). Tim Cox receives Occasional lecture fees for conferences (Shire, Actelion and Genzyme). Principal Investigator clinical trials in Gaucher disease with Actelion and Genzyme. Unrestricted research grant support (modest) in Gaucher disease: Shire and Genzyme. No shares in any company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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