Michael J. Fox Foundation Awards $1.3 Million to Advance Potentially Disease-Modifying Therapeutic Targets for Parkinsonís Disease
Research into disease-modifying therapies is a key priority for MJFF, which seeks to provide patients with scientific solutions beyond currently available treatments that can only mask symptoms as the disease continues to worsen. There is an urgent need for new therapies that could slow or stop PD progression. Current treatments also cause serious side effects and lose their symptomatic effectiveness over time.
Funded projects will advance seven different therapeutic targets at varying stages of development. Teams working on newly discovered targets will work to amass enough initial data to confirm these targetsí role in PD. Those focusing on known targets will work to refine characterization of specific mechanisms of action in order to advance drug development.
Two awardees are focused on the protein alpha-synuclein, whose clumping in the brain is a pathological hallmark of PD. Christine Bulawa, PhD, of FoldRx Pharmaceuticals, Inc., and colleagues have been funded by MJFF since 2007 to identify lead compounds that could prevent the death of dopamine-producing neurons due to a toxic buildup of alpha-synuclein. The group has identified a compound known as J3 that displays protective properties in a cellular PD model. Bulawaís team will now test J3 in yeast models to further examine its effects and determine the specific cellular pathways affected, fostering the development of a viable drug candidate.
Two funded teams will investigate LRRK2, a gene first linked to PD in 2004 and now believed to be the most common genetic contributor to the disease. Andrew West, PhD, of the University of Alabama will advance promising outcomes from an MJFF award he received in 2007 to characterize the relationship between LRRK2 overexpression and dopamine neuron death. Dr. West has created a panel of novel vector-based systems for delivering LRRK2 to the brain. His team will now deliver LRRK2 to the brain of a pre-clinical model and measure the toxic effects on dopamine neurons, with the goal of validating specifically defined aspects of LRRK2 activity as targets for Parkinsonís therapeutic development.
MJFF fast-tracks investigations of non-Parkinsonís drugs already approved by the U.S. Food and Drug Administration (FDA) (or other regulatory agency) that also show potential to benefit Parkinsonís patients. Such drugsí FDA-approved status and established safety profile can accelerate their path toward clinical trials and commercialization for PD. Marina E. Emborg, MD, PhD, of the University of Wisconsin-Madison has been funded by MJFF since 2005 to investigate whether the FDA-approved diabetes drug pioglitazone may slow PD progression. Her team is now developing data that could be used in a future clinical trial in Parkinsonís patients.
A full list of funded awards is below. Grant abstracts and researcher biosketches are available at www.michaeljfox.org.
Elucidating the Mechanism of Action of J3, A Neuroprotective Small-molecule Candidate to Treat Parkinsonís Disease
Christine Bulawa, PhD, FoldRx Pharmaceuticals, Cambridge, Massachusetts†
Evaluation of Neuroprotective Properties of Selective PPAR Gamma Agonist LY554862
Evaluation of Pioglitazone CSF Penetration
Marina E. Emborg, MD, PhD, University of Wisconsin-Madison, Madison, Wisconsin
The Impact of Oligomerization on Alpha-Synuclein Toxicity
Fred H. Gage, PhD, Salk Institute for Biological Studies, La Jolla, California
Analysis of Adhesion and Chemotactic Factor Expression Possibly Involved in T Cell Brain Extravasation in Parkinsonism: Preliminary Studies for a Target Validation
Etienne Hirsch, PhD, French Institute of Health and Medical Research (INSERM), Paris, France
Immunology and Bioactivity of Regulated rAAV1-GDNF in Rodent Models of PD
Ronald J. Mandel, PhD, University of Florida College of Medicine, Gainesville, Florida
LRRK2 Variation in Parkinsonís Disease
Owen A. Ross, PhD, Mayo Clinic, Jacksonville, Florida
Delivery of Kinase-Modified LRRK2 to Dopaminergic Neurons Using High-Capacity Viral Vectors
Andrew West, PhD, University of Alabama, Birmingham, Alabama
Time Course of TNF-alpha Expression and Oxidative Stress after Intrastriatal 6-OHDA
Caryl Sortwell, PhD, Rush University Medical Center, Chicago, Illinois
Validation of TorsinA as a Target for PD Therapy in Mammalian Models
David G. Standaert, MD, PhD, University of Alabama, Birmingham, Alabama