Development of Small Molecule Hepatocyte Growth Factor Mimetics for the Treatment of Parkinsonís Disease
Rapid Response Innovation Awards, 2012
The goal of this project is to determine the clinical potential of a novel, orally active hepatocyte growth factor mimetic for the prevention and/or treatment of Parkinsonís disease in a pre-clinical model.
The project will first investigate the ability of Dihexa, a hepatocyte growth factor activator, to prevent the development of Parkinson-like symptoms in a pre-clinical model of Parkinsonís disease. Motor function and nerve cell health will be monitored. Next we will determine whether Dihexa is capable of restoring motor function in pre-clinical models that are already exhibiting motor deficits. Additionally, we will examine two possible mechanisms: the induction of new connections among remaining nerve cells and the generation of new nerve cells from stem cells already present in the brain.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
The goal of the project is exploit the natural ability of a neurotrophic factor, hepatocyte growth factor, to protect nerve cells from damage in Parkinsonís patients by using orally active small molecule activators. Moreover, it is possible that the use of these activators will not only prevent damage but encourage recovery by repairing damaged connections among nerve cells and stimulating the production of new nerve cells from neural stem cells.
Two positive outcomes are possible from this work. First, Dihexa may prevent the development of Parkinsonís disease in pre-clinical models. In humans we would expect that Dihexa would stop the progression of the disease following diagnosis at any stage. Second, Dihexa could reverse the nerve cell damage initiated by Parkinsonís disease resulting in a recovery of lost function.
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundationís†Partnering Program.
The goal of this project was to begin to evaluate the therapeutic potential of a small molecule activator of a growth factor, hepatocyte growth factor, which is known to protect nerve cells from damage, stimulate new connections among nerve cells, and induce the production of new neurons form stem cells. The hypothesis guiding the study was that the drug candidate Dihexa would be effective at restoring motor function that was lost in a standard pre-clinical model of Parkinsonís disease. The results of this study confirmed this hypothesis, demonstrating that Dihexa, given by abdominal injection or orally, completely restored lost motor function. Moreover, staining for tyrosine hydroxylase (TH), a marker for the dopamine neurons that were lost following chemical lesioning, returned to near normal after 34 days of treatment. Studies are still ongoing to determine whether this recovery of TH staining was due to the presence of new nerve cells and/or the expansion of the appendages of surviving neurons.
Presentations & Publications
Poster at the 7th Annual Drug Discovery for Neurodegeneration Conference: An Intensive Course on Translating Research into Drugs, presented by the Alzheimerís Drug Discovery Foundation, on February 10-12, 2013 in San Francisco, CA.
Location: Pullman, Washington, United States