Parkinson’s Disease Therapies: Genomic Insights and Stem-Cell Innovations

Both genetic and environmental factors cause Parkinson’s disease. This presents challenges for developing therapies that target the underlying causes of the disease. In addition, because individual cases of Parkinson’s do not always progress in the same way, it can be difficult to evaluate treatment efficacy in clinical trials.

Clinicians and clinician-investigators in the Division of Movement Disorders in the Department of Neurology at Brigham and Women’s Hospital are taking various approaches to provide specialty care for patients facing a broad range of diseases that affect movement, including Parkinson’s disease. They are also conducting basic and clinical research to identify the underlying causes of these disorders and generate better treatments. The overarching goal is to develop patient-tailored therapies to prevent or slow down these diseases.

Vikram Khurana, MD, PhD, chief of the Division of Movement Disorders, leads these efforts by integrating genetic and stem-cell technologies into an innovative clinical trial approach.

“The therapeutics that we have in development for Parkinson’s right now fall into two categories,” he says. “First, the many attempts to optimize the treatment of symptoms but not change the outcome of the disease. Second, experimental therapies aiming to slow the disease down that either take an ambitious one-size-fits-all approach or target rare genetic forms of the disease where only a few patients stand to benefit. We look for the middle ground—tailored treatments for patients with the common so-called ‘sporadic’ forms of the disease.”

Modeling Disease Using Gene Editing and Stem Cells

Protein misfolding and aggregation in the neurons and glial cells of the brain are the common denominator in neurodegenerative diseases like Parkinson’s. For Parkinson’s and related disorders, the Khurana Lab maps out all of the genes in the genome that impact the misfolding of a specific culprit protein called alpha-synuclein. Investigators compare these maps to a patient’s own genome, giving them clues as to why the disease arose in each specific patient.

To test whether these genes really do impact the disease process, lab members use a patient’s own stem cells to develop mini-brains, or organoids. The model captures in the dish not only the patient’s own brain cells but also the protein that aggregates. In the case of Parkinson’s, the alpha-synuclein protein can be amplified from the spinal fluid, blood, skin, or even a nasal brushing. What results is a personalized lab model that gives both genetic and environmental clues as to how the disease arose in that patient and what drugs might slow the process down. Since the patients from whom these stem-cell models are modeled are also followed at the Brigham, there are opportunities for innovative clinical trials.

“We use computational biology and genomics to hypothesize whether a particular gene or pathway is important in protein misfolding,” Dr. Khurana says. “To validate whether these hypotheses are correct and whether a particular gene or pathway contributes to someone’s disease, we create a cellular and organoid model of their disease. Then we can use gene editing to determine whether that gene’s activity affects disease progression.”

In a recent study, Khurana’s lab extended these studies to also test the effects of environmental exposures in the dish, including the effects of pesticides, creating a more complete model of both genetic and environmental interactions that lead to disease.

Patient Data Drives the Future of Parkinson’s Disease Clinical Trials

Dr. Khurana has collaborated with geneticists and computational biologists to analyze large datasets generated from patients with Parkinson’s and related disorders. This includes the Harvard Biomarkers Study, which has already tracked more than 1,000 patients with Parkinson’s over time. The study includes a similar number of patients with Alzheimer’s disease and other forms of dementia along with control subjects. These patients are now being analyzed for their potential to participate in clinical trials.

“One of the most exciting things we’re doing right now is that we’ve started a clinical trial incubator within the Division called MyTrial,” Dr. Khurana says. “It’s quite a new way of working with our patients because we are not only caring for their medical needs but also gaining an understanding of the disease, which can help guide future research.”

For a subset of patients being considered for clinical trials, biometric data (de-identified to protect patient privacy) are collected under the program, quantifying patients’ movements and connecting this information with biospecimens and imaging scans to find markers for Parkinson’s. An important goal of collecting these data is to develop new measures for evaluating the efficacy of drugs in clinical trials. This innovative trial approach tests a drug’s ability to shift a patient’s progression trajectory.

People treated under this program are seen at the Hale Building for Transformative Medicine, which brings together the Brigham’s full array of clinical providers and investigators in neuroscience and musculoskeletal research in one location. “Having our labs upstairs and our clinical and imaging facilities downstairs in the same place is very enabling for our work,” Dr. Khurana says.

Understanding the many roads to Parkinson’s disease demands an understanding of an individual patient’s genetic profile and environmental exposures and the nuances of cellular neurodegeneration. The Division of Movement Disorders and Khurana’s lab pursue a dual approach in which patients are closely tracked in the clinic and their stem-cell avatars and genomes are analyzed in the lab. In this way, researchers hope to address the major unmet need for patient-targeted and disease-modifying therapies for Parkinson’s and related disorders.

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