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UPenn Launches Large-Scale Sequencing Initiative to Improve Neurological Disease Detection


NEW YORK (GenomeWeb) – A group of researchers at the University of Pennsylvania Medical School has begun a program to improve diagnostic tools for patients suffering from Parkinson's disease.

Known as the Molecular Integration in Neurological Diagnosis (MIND) initiative, the multi-department team at Penn aims to collect and sequence more than 2,500 blood samples by 2020 to develop diagnostic tools and improve treatment options for patients suffering from Parkinson's disease.

Penn associate neurology professor and project leader Alice Chen-Plotkin explained that the team wants to incorporate molecular data into Penn's current Parkinson's disease genetic database to see if there are specific mutations directly linked to heterogeneity of neurological diseases including Parkinson's.

According to Chen-Plotkin, Penn is using the project as part of its push into precision medicine. The group will apply patient-level data to better match individuals with appropriate therapies, as well as "experimental therapies with patients who will better respond to them." While other researchers have discovered genetic biomarkers for neurological diseases like Parkinson's disease, Chen-Plotkin noted that they've also encountered heterogeneity among several patients.

"You see several therapies coming down the pipeline, but [clinicians] are looking at specific targeting of specificity pathways," Chen-Plotkin noted. However, "it seems unlikely that the pathways are all equally at work, and we [therefore] need to understand things like who [exactly] carries a specific mutation versus another."

Chen-Plotkin said that the researchers have been contacting patients of the university's Parkinson's Disease Center, asking if they would like to enroll in the program and learn about the results afterward.

During the initial visit, Chen-Plotkin's team will draw about four tubes of blood from the patient. Chen-Plotkin explained that the researches will use two tubes for DNA isolation, while the additional two tubes are stored as backup samples.

After DNA extraction, the researchers will sequence across the genes of interest using either exome or whole-genome sequencing tools. They will start by looking to see if patients are carrying mutations in the LRRK2 & GBA genes, since "from a clinical standpoint, those are mutations that we expect there to be a substantial proportion of people carrying them," Chen-Plotkin said.

For patients with potentially actionable mutations, the team will confirm research results in a CLIA-approved testing environment and disclose the information to patients in a genetic counseling center at Penn.

"The initiative is a cross-department project, involving Penn's neurology, precision medicine, and pathology department," Chen-Plotkin said. In this foundation stage, "genetic counselors at Penn will work with patients" to discuss options regarding genetic disclosure.  

Chen-Plotkin noted that Penn's Neurology department and the Penn Center of Precision Medicine are initially funding the MIND initiative. Her team is also exploring avenues to partner with additional funders in the Parkinson's disease space.  

While other groups — such as the National Parkinson's Foundation, the National Institutes of Health, and commercial firms — have launched nationwide projects to sequence DNA of patients with Parkinson's disease, Chen-Plotkin argues that the MIND initiative will stand out due to its envisioned population sample size and goal of incorporating research and clinical workflows.

"If you're looking at a disease, you [normally] have a cohort of several hundred people, which represents less than 10 percent of your clinical population," Chen-Plotkin said. "If you want to offer to patients … something useful … and the field the ability to understand this subgrouping, we need to target everyone, not just a small subset."

However, Chen-Plotkin acknowledged that her team will likely encounter issues related to data challenges and bioethics as it moves forward with the project.

Noting that her team has previously worked on data from large biorepositories such as the Michael J Fox Foundation Parkinson's Disease Initiative and the NIH Parkinson Disease Biomarker Program, Chen-Plotkin pointed out that researchers have yet to develop an effective method to deal with copious amount of data for clinical applications.

"The difficulty is that the people who can code may not know which questions are the best to ask, and so you want to create data in a space that allows people who have deep knowledge of diseases that are involved to access the right questions," Chen-Plotkin explained.

In addition, Chen-Plotkin said that her team is currently grappling with how to appropriately address genetic disclosure with patients. The researchers are therefore studying patients' attitudes about their interest in genetic testing results, and how it impacts their decisions regarding the release their data. 

"People are not clear yet as to where the bioethics are of this program, as you can't just extrapolate data to other diseases, such as Huntington's," Chen-Plotkin said. "We are working through how to offer knowledge to patients in a way that is most beneficial without the risk of harm, and that is going to be challenge for us."

Chen-Plotkin noted that Parkinson's disease patients participating in past studies often have not found out how their cooperation influences clinical practice until years later. Chen-Plotkin's CLIA-approved lab therefore hopes to solve the lack of communication by disclosing genetic results to the patient as soon as possible for potentially improved clinical results.

For the first 18 months, Chen-Plotkin's team will examine blood samples of patients with Parkinson's disease. From there, the researchers will evaluate other neurological diseases that they want to pursue. Chen-Plotkin hopes that the initiative's results will eventually become exportable to other neurological diseases, as well as help doctors make clinical decisions regarding drug treatment.

"[It] depends on what happens in the field over this period of time, and which of our clinicians [would be] ready to shift [to a new disease]," Chen-Plotkin said. "Our sense is that other neurodegenerations will be good avenues for something like this. ALS, for example, has large mendelian subsets that are important and might become increasingly actionable."