Philip LoGrasso, associate professor and senior director for drug discovery at Scripps Florida, will lead the project as principal investigator. LoGrasso, who joined Scripps Florida in 2005, previously held positions at Merck and the NIH.
The new five-year grant will fund research to develop a compound to treat neurodegeneration in Parkinson’s disease. The goal of the project is to bring the potential treatment to the point where Scripps Research and potential partners can file an application for an investigational new drug—the first step in the lengthy clinical trials process required by the U.S. Food and Drug Administration.
An estimated one million Americans are believed to suffer from Parkinson's disease, according to the Parkinson’s Disease Foundation; approximately 40,000 new cases are reported annually. Patients with Parkinson’s suffer from a loss of dopaminergic neurons, the source of dopamine, a neurotransmitter that plays a key role in motor reflexes and cognitition. While some loss of dopaminergic neurons is common, Parkinson’s patients routinely lose more than half.
“Development of a drug that prevents dopaminergic neurodegeneration would be a quantum leap in the clinical treatment of Parkinson’s disease,” LoGrasso said. “All current therapies treat only the symptoms of the disease, not the underlying pathologies. Current treatments also tend to lose therapeutic efficacy over time, or have adverse side effect profiles that make their long-term use difficult.”
A Classic Approach
To develop the new small-molecule compound, LoGrasso will work with a team of Scripps Research scientists. Together, the team represents a range of experience in pharmaceutical preclinical drug development, encompassing the fields of medicinal chemistry, biochemistry, cell biology, structural biology, behavioral pharmacology, drug metabolism and pharmacokinetics, and toxicology.
The team will use what LoGrasso calls a classical pharmaceutical approach to drug development, which involves annual milestones and multiple compound tracking.
“Our research plan is designed to mitigate the risk of developing a single compound that may fail due to specific problems, and to maximize the chance for clinical success by having back-up compounds,” LoGrasso said. “We believe that using this approach to optimize small-molecule inhibitors will create a series of compounds with favorable pharmacokinetic properties and safety profiles.”
The scientists will examine small-molecule compounds that inhibit c-jun-N-terminal kinase 2/3 (JNK 2/3). Pronounced Junk, JNK 2/3 is an important contributor to stress-induced apoptosis (cell death) and has been shown to play a significant role in neuronal survival. As such, the kinase is a highly viable target for drugs to treat neurodegenerative disorders like Parkinson’s disease.
Previous research has shown that small-molecule and peptide inhibitors of the JNK target protect dopaminergic neurons in both acute and chronic models of Parkinson’s disease. Previous research has also shown that the JNK2/3 knockout mouse models—mice that lack the gene for JNK2/3—suffer fewer Parkinson’s-like symptoms.
The scientists hope to identify approximately three compounds that demonstrate in vivo efficacy by the third year, and a top compound by year four of the research program.
“When we’re finished, our aim it is to have a safe, efficacious compound with sufficient preclinical safety data to support human clinical studies,” LoGrasso said.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.
For information:
Keith McKeown
858-784-8134
kmckeown@scripps.edu