Ehud Goldin (NHGRI)
Ellen Sidransky (NHGRI)
Frank Schoenen (University of Kansas)
Noel Southall (NCATS)
Samarjit Patnaik (NCATS)
Steven Rogers (University of Kansas)
Wei Zheng (NCATS)
Wendy Westbroek (NHGRI)
- In vitro data available
Gaucher disease is a rare lysosomal storage disease that is characterized by a loss of function of the glucocerebrosidase (GCase) enzyme, which results in a decreased ability to degrade its lipid substrate, glucocerebroside. The intracellular build up of this lipid causes a broad range of clinical manifestations, ranging from enlarged spleen/liver and anemia to neurodegeneration. In Gaucher disease, the loss of GCase function has been attributed to low levels of the protein in the lysosomal compartment, resulting from improper GCase folding and transport. Also, mutations in the GCase gene have been linked to some forms of Parkinson's disease, and may also be involved in other proteinopathies.
This technology describes a collection of salicylic acid-derived small molecules that act as chaperones to activate proper GCase folding and subsequent transport from the endoplasmic reticulum into the lysosome. Unlike many other small molecule chaperones, these salicylic acid derivatives do not inhibit the activity of the GCase enzyme. These small molecules have been tested for the ability to activate GCase in vitro and show chaperone activity in a patient-derived fibroblast translocation assay.
- Treatment of Gaucher disease
- Treatment of Parkinson’s disease
- Treatment of other lysosomal storage diseases
- The compounds are novel small molecules that enhance proper GCase folding and transport without inhibiting enzyme activity in the lysosome.