Cell Assays to Measure Peripheral Response to GCase Activators
Therapeutic Pipeline Program, 2014
Objective/Rationale: † † † † † ††
Individuals who carry one copy of the gene for Gaucherís disease are at significantly increased risk of Parkinsonís disease. Lysosomal Therapeutics Inc. (LTI) is developing a drug to correct the biochemical deficit caused by this gene. The goal of this project is to identify those Parkinsonís patients who, despite lacking the Gaucher gene, share the key biochemical deficit. These individuals would potentially be responsive to our therapeutic strategy.
Blood will be drawn from Parkinsonís disease patients and one blood cell type (monocytes) will be isolated. These cells contain glucocerebrosidase (GCase), the product of the Gaucher gene, as well as alpha-synuclein, a protein implicated in PD. As a first step, we will measure the activity of GCase (low activity is caused by the Gaucher gene) and the amount of alpha-synuclein (elevated amount is linked to PD risk). Next, we will treat these cells with our LTI drug candidates. Our goal is to determine which properties predict whether these cells respond to our candidate drugs. This method could be used to enroll patients in and optimize our chances for success in our clinical trials.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † †
It is unlikely that all cases of PD are caused by the same biochemical defect, so it will be important to develop drugs aimed at each contributor. These drugs will only be effective in subsets of patients, so in order to demonstrate success in a clinical trial, it will be necessary to subdivide patients based on their underlying biology, much like is currently done with breast cancer patients. This project begins our efforts to identify patients who are likely to respond to our therapeutic strategy, which is aimed at normalizing the activity of the Gaucher disease gene product.
Anticipated Outcome: † † † † †
If successful, this project will uncover a candidate biochemical marker that can be made in patient blood that will predict whether they will respond to the LTI drug. Confirmation of this marker will require a large-scale study.†
Although Parkinsonís disease patients share some symptoms, the disease is quite hetereogenous, that is, it can manifest in different ways in different individuals.† This is true also of the underlying causes (there are clearly more that one); defects that cause disease in some individuals are benign in others.† For example, mutations in the gene encoding glucocerebrosidase (GCase) increase risk of Parkinsonís disease by approximately five-fold, indicating that normalizing GCase may be an effective therapeutic strategy.† But it is also the case that most patients carrying GCase mutations will never be diagnosed with PD.† This project aims to understand why some individuals are sensitive to GCase mutations while others are not.†
At Lysosomal Therapeutics, Inc., this question is particularly important, since we are developing a GCase-targeted drug for PD.† It will be important to distinguish those patients who are likely to respond to our drug from those who are unlikely to respond.† We have developed a method to determine an individualís ex vivo drug response, in donated white blood cells (PBMCs), as a first step towards enriching our patient population and optimizing the average in vivo response of the clinical population.† This method is now being applied to large and diverse PD populations.
Chief Scientific Officer at Lysosomal Therapeutics, Inc.
Professor of Neurology at Harvard Medical School
Location: Cambridge, Massachusetts, United States
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