Next-generation microbiome medicine may revolutionize the treatment of Parkinson’s and similar disorders

The age-old advice to “trust your gut” could soon take on new meaning for people diagnosed with Parkinson’s Disease, thanks to a creative feat of bioengineering by researchers in the University of Georgia’s College of Veterinary Medicine.

Anumantha Kanthasamy, professor and director of the Isakson Center for Neurological Disease Research (ICNDR) leads a multidisciplinary research team including Gregory Phillips, Piyush Padhi, and other scientists that has engineered a groundbreaking living medicine, a beneficial probiotic designed to deliver Levodopa steadily from the gut to the brain of Parkinson’s patients.

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In a paper published in the journal Cell Host & Microbe, Kanthasamy’s team details how they engineered and tested the probiotic bacterium Escherichia coli Nissle 1917 as a drug-delivery system that continuously produces and delivers the gold-standard Parkinson’s drug, which is converted to dopamine in the brain. E. coli Nissle strain was chosen for its century-long record of safely treating gastrointestinal disorders in humans.

Parkinson’s is caused by the loss of dopamine-producing nerve cells in the brain. Dopamine is a neurotransmitter that governs movement and other functions.

Motor symptoms

Levodopa (L-DOPA), as a pill, has been used for decades to treat the motor symptoms of Parkinson’s, such as slow movement, tremor, rigidity, and balance problems. Ironically, prolonged use of the drug can cause an unpredictable return of motor symptoms requiring multiple daily doses. Over time, this can lead to dyskinesia, characterized by involuntary movements of the neck, trunk, limbs, and face. Dyskinesia, often mistaken for a symptom of Parkinson’s, is caused by L-DOPA entering the blood in waves, causing ups and downs in brain dopamine levels between doses.

“This work represents the first therapeutic application of engineered live biotherapeutics for non-invasive, sustained delivery of L-DOPA drug to the brain in Parkinson’s disease,” Kanthasamy said. “Ultimately, this platform lays the foundation for L-DOPA and other neurochemical-based live biotherapeutics as a continuous, non-invasive drug delivery strategy for PD and other chronic neurological disorders, including Alzheimer-related dementia.”

Padhi, a postdoctoral scientist in the Kanthasamy lab, cited recent advances in synthetic biology and the growing body of scientific evidence linking gut-brain dysfunction to neurological disorders as the inspiration for the study he led.

Natural chemical factories

“Gut microbes function as natural chemical factories, constantly producing metabolites in response to environmental cues,” Padhi said. “Leveraging this principle, we questioned why we couldn’t apply this strategy to overcome the drug-level fluctuations faced by Parkinson’s patients. This new living therapy could mean fewer pills, steadier symptom control, and better quality of life for people with Parkinson’s disease.”

Developing “living drugs,” as Kanthasamy’s team refers to their work, has implications for treating neurological and related gastrointestinal diseases, such as Crohn’s. The efforts unite microbiologists and neuropharmacologists to research the causes and treatments for such illnesses.

For this study, the lab partnered with the Departments of Physiology and Pharmacology, Pathology, and Infectious Diseases at the UGA College of Veterinary Medicine, as well as the Department of Statistics in UGA’s Franklin College of Arts and Sciences. The early phase of this work was conducted by Kanthasamy’s team at the Iowa State University College of Veterinary Medicine.

“The preclinical findings for this L-DOPA engineered live-biotherapeutic suggest we are ready for testing in human clinical trials,” Padhi said.