It’s no secret that harmful mutations to the BRCA1 and BRCA2 genes, which increase a woman’s chances of getting breast cancer, are more common among those of Ashkenazic descent. Now researchers are investigating another gene mutation with links to Jews descending from Eastern Europe, this time related to Parkinson’s disease.
A major international study currently is enrolling participants of Ashkenazic heritage and other risk factors, with local testing taking place at the University of California, San Diego (UCSD). Its focus: the LRRK2 gene, a certain mutation of which is much more common in Ashkenazic Jews and a target of interest in drug development.
It’s all part of a landmark effort that the Michael J. Fox Foundation for Parkinson’s Research began in 2010, called the Parkinson’s Progression Markers Initiative (PPMI). The $60 million international program aims to identify biomarkers in individuals with Parkinson’s, which has no cure and is characterized by tremors, impaired balance and rigidity. In the United States, about 60,000 Americans are diagnosed with the disease each year, according to the Parkinson’s Disease Foundation.
Efforts to identify therapies and medications have been slow to come, and complicating matters is the fact that there are no biomarkers — measurable substances, processes or characteristics of the body (think of the relationship between cholesterol and heart disease) — which are critical in testing new therapies and treatments. Biomarkers give researchers a quick and more effective way to evaluate if a new therapy or drug is working.
With several promising Parkinson’s drugs currently in the pre-clinical phase, “our concern and rationale was that if a therapeutic doesn’t work, we should know that because the therapy isn’t accomplishing its goals. We don’t want the outcomes to be unknown because we can’t measure it,” said Sohini Chowdhury, senior vice president of research partnerships for the Michael J. Fox Foundation.
The current method to gauge the effectiveness of Parkinson’s treatments involves a physician measuring a person’s motions over a specified amount of time, which Chowdhury called highly inaccurate.
“You need a measure that gives you a sense of accuracy and confidence,” she said.
The first wave of PPMI studied individuals with Parkinson’s against a control group. That recruitment ended in 2013 – though the research is ongoing – when the study expanded to groups with non-genetic risk factors, such as REM sleep disorders, and, more recently, to individuals with genetic risk factors, including LRRK2. The current study involving genetic markers is expected to enroll 500 individuals nationwide.
Changes in LRRK2 are believed to be responsible for 15 to 20 percent of Parkinson’s disease cases in Ashkenazic Jews, a much greater percentage than in the general population according to the Michael J. Fox Foundation.
Dr. Douglas Galasko of the UCSD School of Medicine said he and his team are enrolling Ashkenazic Jews who have a family member with Parkinson’s and who are willing to be tested to some degree. The more intensive testing involves spinal taps, brain imaging and more, and they hope to find 50 to 60 individuals worldwide to undergo that level of testing (two or three in Southern California).
Others who want to become part of a registry and learn if they are a potential carrier of the LRRK2 gene — to remain up to date on treatment options as they become available — can do a quick cheek swab test as part of a mail-in kit. Those interested in enrolling in the study or getting tested can find additional details at michaeljfox.org/ppmi/genetics. UCSD is the only site for PPMI in Southern California.
Galasko has high hopes for the study’s potential. He pointed to a recent consortium of efforts to identify biomarkers in people at risk for Alzheimer’s disease, which proved to be successful in just seven years, and which helped standardize markers to be used in research studies and clinical trials.
“It’s made a real difference, and we’re hoping to push the field forward in Parkinson’s as well,” he said. “Being a part of these efforts is very exciting.”
Alon Friedman, associate professor on the faculty of health sciences at Ben-Gurion University of the Negev in Israel, wrote in an e-mail to the Journal that studying genetic markers is an interesting and promising approach.
“First, there is an urgent need for early diagnosis, to be able in the future to prevent the diseases or delay the symptoms, rather than to treat once the cells have degenerated and it is too late. The discovery of biomarkers will be the key for future preventive medicine,” he wrote. “Not less important is the fact that genetic/biomarker studies might reveal new mechanisms that we currently do not suspect, underlying disease generation. The discovery of such new mechanisms will lead to new treatments.”
While there were independent efforts to look for Parkinson’s biomarkers before, there wasn’t one group that could convene everyone on the grand scale of PPMI, according to Chowdhury. This is the Michael J. Fox Foundation’s largest investment to date.
“What differentiates PPMI is the richness and potential of the resources; data is collected and being made available in real time to the research community,” Chowdhury said.
To date, the results have had more than 165,000 downloads worldwide, and the foundation has received 36 specimen requests. Almost anyone can request data from the Web site, ppmi-info.org.
“The whole goal is to make this information available in real time,” she said. “Who knows who will have the next big idea?”