Gauchers Disease

​

Gauchers Disease (GD)  is a rare, lysosomal storage disease with a prevalence of 1 in 57,000 births. The hallmark feature of GD is a deficiency in the β-glucocerebrosidase enzyme (GCase) caused by mutations in the GBA1 enzyme gene that reduces its activity.  This deficiency results in the build-up of the toxic sphingolipid substrates glucosylceramide (GluCer) and glucosylsphingosine (GluSph) that are metabolized by GCase and play an integral part in disease pathophysiology. Three GD subtypes exist: GD1 affecting the periphery, and GD2 and GD3 affecting the brain (neural GD) all of which are lethal.  GD3 has a juvenile or early adult onset with patients living into early teens or adulthood.  Onset of GD2, the most severe form of the disease, begins within 6 months of birth and progresses rapidly resulting in death within two years of age.  Furthermore, between 5-15% of Parkinsons’s patients also have a mutation in the GBA1 gene (GBA-PD). The loss of GCase activity and lysosomal dysfunction may impair alpha-synuclein metabolism. GBA-PD patients have earlier disease onset, more frequent cognitive impairment, and more rapid disease progression. 

​

The Need: An Effective Therapy For Brain GBA1 Enzyme Deficiency

​

Presently, no cure or treatment is available for patients with nGD. As such, there is a critical need to pursue novel strategies to discover and develop effective treatments for neural GD which may also have utility for Parkinson’s GBA-PD as well.  Previous therapeutic strategies to develop small molecule drugs have targeted low GCase enzyme activity to identify “chaperones” for stabilizing the misfolded enzyme or agents to reduce substrate accumulation by inhibiting glucosylceramide synthase that produces the toxic GluCer. Current drugs are effective for peripheral GD1, but due to lack of CNS penetration do not work for neural GD.  Examples include eliglustat (Cerdelga™) and miglustat (Zavesca®) for treatment of GD1. Enzyme replacement therapy (ERT) using recombinant GCase (Cerezyme®) has a significant impact on GD1, yet has no effectiveness in nGD.

​

Lead Compounds Developed Using Novel Patient Cell-Based Assay 

​

Impaired calcium homeostasis and reduction in lysosomal calcium stores is a cellular characteristic seen in both Gaucher and Parkinson’s GBA1-PD patient cells.  A high-throughput phenotypic screen using patient-derived fibroblast cells was optimized to identify small molecules as potential leads for further medicinal chemistry structure-activity studies. 

​

Detection of differences in lysosomal calcium release between patient and normal, healthy cells is used to identify active compounds.  Modification of the structures from several initial “hits” resulted in the synthesis of several potent lead compounds that displayed the ability to penetrate into the CNS with a good pharmacokinetic profile and metabolic stability.  The next step is to evaluate the effect of these lead compounds in an animal model of neural GD, then to continue medicinal chemistry optimization.