Precision Medicine for Parkinson’s Disease Is Focus of New Yale Center

Clemens Scherzer, MD, is on a mission to revolutionize the treatment of Parkinson’s disease through the use of genomics and artificial intelligence (AI) to create tailored therapeutics. In January, Scherzer joined Yale School of Medicine (YSM) and stepped into his new role as director of the Stephen & Denise Adams Center for Parkinson’s Disease Research. The center’s unique approach to developing the future of precision medicine for Parkinson’s disease is the first of its kind, he says.

“Right now, we wait for Parkinson’s disease to progress and cause debilitating symptoms that drive the patient to the clinic, where we scramble to catch up with treating them,” says Scherzer. “Through our new center, we want to learn to catch the disease early, be able to predict what the future will hold for each patient, and then intervene to prevent debilitating progression from ever occurring.”

Scherzer envisions a future in which a person with Parkinson’s disease can walk into a clinic and provide a few drops of blood that a computer program can analyze to identify the patient’s genome and biomolecules. Clinicians would be able to use this information in addition to the patient’s electronic health data to determine the exact disease driver and to recommend precision therapeutics based on tailored biomarkers.

“Our work is similar to how a search engine targets advertisements to a user based on massive search histories,” he explains. “The goal is to precisely match the right drug to the right person at the right time, based on a search of the entire disease biology.”

To make this vision a reality, Scherzer and his team are building a multi-modal human atlas of Parkinson’s disease by cataloging molecular and clinical data from thousands of patients. Scherzer began this work while at Harvard Medical School, where he was professor of neurology, director of the American Parkinson’s Disease Association (APDA) Center for Advanced Parkinson Research, and director of the Precision Neurology Program at Brigham and Women’s Hospital. He will be advancing these efforts at YSM.

So far, Scherzer’s team has already sequenced the RNA programs of one million human brain cells spanning the entirety of disease progression—from healthy brains, to those in the earliest stages of Parkinson’s, to those in the most advanced manifestations of the disease.

Other ongoing work that also will be expanding at the Yale center includes the Yale Harvard Biomarkers Study, which involves mapping the genetic variants that control the course of Parkinson’s and using multi-omics technology to catalog molecules in patients’ biofluids. The biobank already has hundreds of thousands patient samples of DNA, RNA, plasma, and more—stored at the Yale Adams Center and with collaborators at Mass General Brigham—that he and his program have extensively characterized over several years as patients’ disease advanced. “This is a treasure trove for discovery of genes, therapeutics, and biomarkers,” says Scherzer.

For example, approximately 10% of patients with sporadic Parkinson’s disease [in which the patient has no clear familial history] have a mutation in a gene known as GBA. Researchers have discovered four different types of genetic variants of this gene that regulate the speed of progression of the disease. Those with the most severe mutation suffer a very rapid progression of their condition. After identifying this disease driver, a research team Scherzer led at Harvard collaborated with a pharmaceutical company to target this gene with precision medicine. The collaboration contributed to the first Phase 2 clinical trial focused on a genetic form of Parkinson’s and provided a tool kit for precision trials targeting GBA.

Scherzer hopes to use the power of genomics and AI to turn data into medicine. The center is using computational neuroscience and machine learning to accelerate research. “With powerful sequencing and computational technologies, we can look at 30,000 genes in a million brain cells in parallel and let biology tell us what is truly important to work on.”

Now, Scherzer’s ambitions include identifying other disease drivers and learning how to target them. “We’re on a quest to decode the RNA software of brain cells and figure out how to develop tailored drugs that correct any glitches,” he says. “Then, our goal is to launch early-stage clinical trials based on our newly identified drug targets.”

To fast-track drug development, the researchers are utilizing electronic patient data from entire populations and from their Yale Harvard Biomarkers Study to find old drugs that could be repurposed for Parkinson’s patients. In collaboration with the University of Bergen in Norway, Clemens’ team is using computer models to compare health outcomes recorded over a decade in thousands of individuals with Parkinson’s disease on a medication compared to millions of individuals with Parkinson’s not on the medication. “We are searching for old drugs that can be taught new tricks to help patients with Parkinson’s disease,” says Scherzer.

This search is identifying drugs for possible repurposing, including medications commonly used for asthma known as beta2 agonists. In the lab, the researchers observed that in neurons grown in a dish, the asthma drugs lowered the activity of the alpha-synuclein gene and improved the cells’ health. “This was intriguing because the brains of Parkinson’s patients are full of Lewy bodies, which are piles of alpha-synuclein,” says Scherzer. “Dialing down alpha-synuclein levels would be ideal to correct this disease driver.”

Several beta2 agonists are currently in clinical trials. Scherzer and colleagues hope that their repurposing platform will spur even more clinical trials.

A central goal of the Yale center is to develop new and more effective Parkinson’s disease medications that slow or block disease progression and prevent disabling symptoms from ever occurring. “We already have dopamine replacement medicines that treat patients very well for several years, but then debilitating complications develop,” says Scherzer. “If we can identify drugs that extend this therapeutic window for 10 years or more, many patients will never suffer these complications.”

His longer-term vision is to one day build a precision neurology clinic where those living with Parkinson’s disease receive personalized treatments. “We are going to change patients’ lives,” says Scherzer.