Targeting Internalization and Aggregation of Alpha-synuclein Proteopathic Seeds with Glycosaminoglycan Interacting Small Molecules (GISMO)
Target Validation, 2014
Objective/Rationale: † † † † †
Evidence points to key roles for alpha-synuclein and cell-surface glycosaminoglycans (GAGs) ó a type of carbohydrate molecules ó in the onset of neurodegenerative diseases. This project aims to demonstrate:
- internalization and aggregation of alpha-synuclein by nerve cells is mediated by heparan sulfate GAGs (HS-GAGs),
- and that process can be inhibited by a newly discovered class of compounds (GISMO compounds) that interfere with the binding of alpha-synuclein to GAGs,
- and the inhibition of this process has the potential to protect nerve cells.
We have identified a series of compounds that act as inhibitors to HS-GAG binding proteins. Initially, we will test these compounds to identify which specifically prevent alpha-synuclein interaction with HS-GAGs. Further, we will determine whether these compounds protect cells from the damaging effects of abnormal alpha-synuclein.† Compounds that pass these tests will then be tested in a pre-clinical model to test for reduction of alpha-synuclein spread.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
Our ultimate goal is to develop a disease-modifying treatment for patients diagnosed with Parkinsonís disease (PD). We believe that this work will also contribute to overall understanding of PD pathogenesis, leading to additional treatments that target other aspects of the disease. Our hope is that treatments can work together at an early stage of disease. † † † † ††
Anticipated Outcome: † † † † †
We expect to identify compounds that show anatomical evidence of disease-modification. We foresee that selected compounds could be further tested in PD pre-clinical models to determine efficacy against disease progression over time as well as improvement of motor aspects of the disease.
Chief Executive Officer and Chief Scientific Officer at Gismo Therapeutics, Inc.
Location: Queens, New York, United States
VARI Associate Director of Research; Director at Center for Neurodegenerative Science
Location: Grand Rapids, Michigan, United States