The Parkinson's Progression Markers Initiative (PPMI), a large-scale biomarker study sponsored by The Michael J. Fox Foundation for Parkinson's Research (MJFF), is expanding to study individuals with genetic mutations associated with Parkinson's disease (PD). Researchers hope that greater understanding of the biology and clinical features of these participants—people with or at risk to develop Parkinson's—will lead to therapeutics that would help all Parkinson's patients and ultimately provide strategies to prevent disease onset.
"Focusing on PD patients and those at risk for PD with genetic mutations will allow us to track the disease process at the earliest stages of illness," said Ken Marek, M.D., principal investigator of PPMI and president and senior scientist at the Institute for Neurodegenerative Disorders in New Haven, Conn. "This population will teach us about the biology of Parkinson's disease and will accelerate our research toward a PD biomarker and more effective PD therapies."
The trial will enroll individuals with a mutation of the LRRK2 or SNCA gene. The LRRK2 protein kinase and the alpha-synuclein protein, encoded by the LRRK2 and SNCA genes respectively, are two of the greatest targets of interest in PD drug development. A mutation in the LRRK2 gene may heighten activity of the LRRK2 protein kinase, which modifies other proteins important in PD pathology. The normal function of alpha-synuclein is not yet known, but clumps of this protein found in the cells of all Parkinson's patients may be a cause of brain dysfunction.
The functional understanding of LRRK2, the ubiquity of alpha-synuclein aggregation and the genetic association of both make them foci of therapeutic programs at several pharmaceutical companies. However, missing from the development pipeline is a key tool to measure a drug's effect on disease; a biomarker would allow researchers to quickly and objectively measure a therapy's ability to slow, halt or reverse the Parkinson's process.
PPMI is studying clinical and imaging data and biological samples of people with a genetic mutation to identify biomarkers and speed clinical trials. In addition, when a drug targeting LRRK2 is ready for clinical testing, this study will have assembled a group of people with this mutation for participation in studies. Alpha-synuclein therapies can be tested in all Parkinson's patients, but individuals with the SNCA mutation present another population of interest to study the effects of candidate drugs.
PPMI will enroll 250 people with the LRRK2 mutation and Parkinson's and 250 people with the mutation but without Parkinson's. Since the SNCA mutation is rarer, the study is recruiting 50 people with Parkinson's and the mutation and 50 people with the SNCA mutation but without PD. These participants will be followed for five years.
By collecting data and samples over time from people who have not been diagnosed with the disease but who carry an associated genetic mutation, researchers can test for characteristics that may denote greater risk of disease onset or, conversely, protection from symptoms.
The genetics of Parkinson's is a relatively new area of study. Two decades ago, the disease was thought to have no genetic component. In 1997 researchers found that several families with a high prevalence of Parkinson's had mutations in the SNCA gene. That information ultimately led to the finding that all PD patients show cellular alpha-synuclein aggregation. By continuing the study of familial Parkinson's, researchers discovered the LRRK2 gene's correlation with PD in 2004. Scientists are still investigating the role of the LRRK2 kinase in Parkinson's disease.
Although known genetic mutations currently account for only 5% to 10% of all Parkinson's cases, study of these individuals may reveal disease traits that apply to all PD patients. The PPMI genetic cohort will expand understanding of the pathogenesis of both genetic and idiopathic Parkinson's disease.
Launched in 2010, PPMI is a longitudinal clinical study that collects standardized clinical, imaging and biologic data. Now taking place at 32 clinical sites around the world, the study completed initial enrollment of 423 recently diagnosed Parkinson's patients and 196 controls in April 2013.
"We're studying multiple cohorts—Parkinson's patients, populations with genetic and other risk factors—in a sort of full-court press to find and validate these biomarkers. We hope this expanded study of people who carry PD genetic mutations will mean better therapies for people living with the disease today and for the many more who will soon be at risk as our population ages," said Todd Sherer, Ph.D., MJFF CEO.