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Parkinson's Foundation Project Seeks to ID Patient Disease Variants to Guide Therapy


NEW YORK – The Parkinson's Foundation has launched a nationwide genetics project that will analyze potential biomarkers for Parkinson's disease (PD) to improve clinical care and offer new treatment options for patients. Called PD GENEration: Mapping the Future of Parkinson's Disease, the initiative will include sequencing efforts from Fulgent Genetics and database management support from several academic institutions.

The multi-center effort will begin with an initial pilot study at Columbia University next week, where the team aims to collect 600 PD patient samples before expanding to a larger cohort of 15,000 patients by 2024.

"There is this hope and promise of precision medicine for PD; however, we don't know the patient population who could take advantage of it," Parkinson's Foundation CSO James Beck said. "We are in the process of making sure that everyone is aware of the results of clinical tests and that researchers will be able to use the wealth of information later on."

Parkinson's Foundation CEO John Lehr explained that the initiative started as an idea in 2018 between Beck and Columbia neurology professor and PF scientific advisory board member Roy Alcalay. The team saw that sequencing technology had advanced enough that researchers could start testing patients for two PD mutations that could act as potential predictors of the disease. However, Lehr noted that the foundation needed to build a clinical infrastructure involving several academic entities, commercial partners, and more before moving forward with the project.

According to Beck, the group aims to achieve three major goals with the initiative: to accelerate current clinical trials that PD patients may not be aware of, to create the largest active PD database linking genetic status to clinical status, and to provide insight into disease progression and symptom severity, which the foundation believes might help influence clinical and treatment options.

"We're trying to dissuade pharmaceutical companies from doing the genetic studies on their own," Beck said. "It's our concern that they will lock up this information on their own and not share it with others if the study doesn't work out," which he emphasized may leave patients in the dark about their own results.

As part of improving the efficiency of clinical trials, the foundation will offer genetic testing at select centers of excellence across the US. At each center, a doctor will draw two tubes of about 4 ml of blood from a patient during a clinical visit.

Clinicians will send the tubes to Fulgent's Los Angeles-based CLIA-approved/CAP-accredited laboratory, where researchers will process the samples by extracting DNA and sequencing the genes for biomarkers often linked to the condition using a customized version of the firm's research-use-only PD next-generation sequencing assay.

The researchers will first seek to identify patients with mutational variants of the LRRK2 and GBA genes, which Lehr said are found in about 10 to 15 percent of patients. "With these two mutations, it's a game changer, because up until 10 years ago, people didn't think there was a genetic element in Parkinson's," Lehr said.

In addition, he noted, researchers have identified 20-plus genes potentially related to the condition. Beck said Fulgent will use the customized next-generation sequencing panel to also find aberrations in SNCA, PRKN, PINK1, PARKN, and VPS35 genes.

Fulgent CSO Harry Gao highlighted that the targeted PD panel was developed through a prior collaboration between Fulgent's researchers and the Parkinson's Foundation's steering committee.

Gao also noted that Fulgent's standard PD NGS panel includes 26 genes associated with an increased risk of developing PD. The panel can run on Illumina's HiSeq and NovaSeq platforms, and Fulgent said it can deliver a throughput of between 1,500 and 2,000 samples per day.

After running the data through a proprietary bioinformatic analysis, Gao and his team will de-identify and upload the results as part of a customized CLIA-certified report — containing likely pathogenic variants — to the Research Electronic Data Capture database that the treating clinicians, genetic counselors and patients can access via a secure, customized online portal.

While the Parkinson's Foundation is spearheading the study through its network of 36 centers of excellence, Beck said the team is also partnering with Columbia and other undisclosed academic groups to collect patient samples.

Beck argued that the PDGeneration initiative will differ from past efforts to collect PD genetic information because the group will also offer free genetic counseling to patients as part of the study. In addition, he said that the genetic testing will be complete and comprehensive for all genes the team seeks to analyze as part of the initiative.

The organization is also working with the University of Florida's Clinical and Translational Science Institute, University of Rochester Clinical Trials Coordination Center, and Indiana University as part of the study's downstream clinical workflow.

According to Gao, the University of Florida's CTSI will help manage and secure the PD data on REDCap as a means to centralize the study genetic reports and documents. TPD patients will receive genetic counseling either with an onsite clinician or through telegenetic counseling services offered by Indiana University.

Gao said that the total turnaround time from receipt of sample at Fulgent to delivery of the report will be about three to four weeks, which includes any additional lab work for confirmatory testing.

Beck explained that the Parkinson's Foundation selected Fulgent as its commercial genetic testing partner because they previously worked together to validate Fulgent's PD-related panels, sending a number of blinded samples to test for genes that are particularly difficult to sequence in PD. Beck said that the foundation is therefore confident in the firm's ability to sequence a large number of samples during the multi-year project.

According to Beck, the initial phase of PD GENEration will exclusively occur in the US, potentially later followed by group sites around the world. The group will begin by launching a pilot study at Columbia University next week, where the team will collect 600 patient samples this year before expanding the study to 15,000 patients at multiple US partner sites by 2024. Beck noted that the study is "in essence" an extension of the group's current Parkinson's Outcome Project, as some of the patients enrolled in POP will also input their genetic information in the new study.

"People would have been reluctant to participate... if we had done this study two years ago, because simply getting genetic information analyzed and finding out you have a genetic form of PD, yet not being able to do anything about it is, is really disheartening," Beck said. "We're now at a point where there's a call to action that getting your genes tested to understand whether you have a genetic form of PD could lead to an enrollment in a clinical trial."

Beck explained that clinicians broadly cannot prescribe effective therapies for most individuals diagnosed with PD. By assembling large datasets of phenotypic and genotypic information, Beck believes that clinicians may eventually be able to establish connections between a patient's phenotypic behaviors and their genetic mutations.

Lehr also hopes that the team will begin to see patterns for PD diagnosis and prognosis.

"While we know that [LRRK2 and GBA] can present differently in patients, it will be interesting to see if other genetic mutations present differently as well," Lehr said.

Beck also noted that the foundation wants to use actionable genetic information to help PD patients understand their disease progression and symptom severity. If patients learn that they have a genetic form of the disease that can be identified by the panel, Beck believes that they may feel assured of their diagnosis and potentially seek genetic therapy that is effective for their mutation-specific form.

Beck highlighted that early research showed that patients with LRRK2 mutations appear to have a slower disease progression and less cognitive involvement. If the patients experience motor-based complications, neurologists may recommend patients undergo deep brain stimulation surgery, a common intervention for the disease.

"Right now, there's a hint that some people with a genetic PD may have a lower progression status than on average," Beck noted. "That could provide some info to the doctor, who can react accordingly and recommend therapies that might be contraindicated for a different form of genetic PD."

In contrast, Beck pointed out that preliminary data suggests that patients with a genetic form of PD caused by a GBA mutation may have, on average, a slightly faster progressing form of the disease and greater cognitive involvement. As a result, clinicians may in the future exercise some caution in terms of therapeutic treatments for these particular forms of PD.

Lehr said that the Parkinson's Foundation is paying Fulgent for its part of the project, which includes processing, sequencing, and storing the DNA samples for patients in the database.
According to Lehr, the foundation is seeking to raise about $15 to $20 million over the course of the five year initiative to pay for sequencing and data analysis support from academic collaborators.

"The key with this initiative is that for people with PD, genetic counseling and sequencing tests are free, as we believe that the combination of genetic and clinical information will help open new avenues of discovery," Lehr said.