Pamela J. McLean, Ph.D.
Can you describe your drug development project?
My lab is interested in developing therapeutics for Parkinson's disease and related disorders, collectively known as synucleinopathies. These diseases are named for the accumulation of a protein in the brain called alpha-synuclein, which leads to neurodegeneration.
Alpha-synuclein is implicated in synucleinopathies for several reasons, including the fact that mutations in the gene encoding alpha-synuclein result in inherited forms of Parkinson's disease.
My lab has been studying mechanisms of alpha-synuclein aggregation for many years. We have developed assays to monitor the aggregation process in cultured cells, as well as in the brains of rodents. Using these assays, we are trying to identify small molecule compounds that can reduce alpha-synuclein-alpha-synuclein interactions, the first step in the aggregation process, with the goal of reducing alpha-synuclein accumulation in the brain and halting progression of disease.
What motivated you to get involved in this work?
I have been working on alpha-synuclein biology for the past 17 years, ever since the first mutation in the alpha-synuclein gene was discovered. Although treatments exist to manage the symptoms of Parkinson's disease, there are currently no disease-modifying therapies that can stop the progression of the disease at a time when patients could still lead a full, active life.
Parkinson's disease is a devastating disorder with poorly understood causes. Although famously known as a movement disorder, many people with Parkinson's disease will go on to develop dementia in later stages of the disease.
I was motivated to become involved in drug discovery projects because the goal of my work is to make scientific discoveries that will lead to the development of new therapies to treat patients. The opportunity to translate our research findings and apply them to drug discovery is exciting and challenging because of the ultimate motivation — the patients suffering from these diseases.
What do you hope to accomplish with this project?
If our drug discovery project is successful, we hope to identify one or more classes of chemicals that are able to reduce alpha-synuclein-alpha-synuclein interactions. This is challenging because in order for drugs to access the brain, they must have a small chemical structure. Once we identify suitable chemicals, we will work with chemists to subtly alter the chemical structure to make them effective drugs.
The ultimate goal of the project is to identify, modify and characterize a compound that can then be advanced to phase I clinical trials for prevention of synucleinopathies.
How do you see this project eventually improving patient care?
The availability of an effective disease-modifying drug for Parkinson's disease and related disorders will be huge. Although a cure for these diseases would be wonderful, we are realistic and recognize that the diseases are complex and will be extremely challenging to cure, not to mention it may take a long time.
In the meantime, our best strategy is to find ways to identify patients at risk of developing Parkinson's disease and offer a treatment that can prevent the progression of the disease. When patients are first diagnosed, they are often in the early stages of the disease. Although the brain may have some deterioration at that point, if we halt further deterioration, patients will be able to live the remainder of their lives with relatively few symptoms.
How has the CCaTS Drug Discovery and Development resource aided your work?
The CCaTS Drug Discovery and Development resource has provided important initial funds for my drug discovery project. With these funds, we established a collaboration between my lab and the drug screening facility at Sanford-Burnham Medical Research Institute in Lake Nona, Florida.
The partnership has been very successful, and initial drug discovery efforts funded by CCaTS have resulted in additional extramural funding from the state of Florida and the Michael J. Fox Foundation for Parkinson's Research to perform extensive drug screens of more than 1 million compounds.