Researchers harness probiotic bacteria to offer treatment for Parkinson’s disease

Animal studies show that live biotherapeutic products produced by gut-healthy probiotic bacteria are safe and reduce treatment complications.

The researchers designed probiotic bacteria capable of synthesizing the dopamine precursor L-DOPA, a powerful basic treatment for Parkinson’s disease. Preclinical tests show that the new therapeutic approach is not only safe and well tolerated, but also eliminates the side effects that eventually develop when L-DOPA is taken orally.

“We are harnessing the metabolic capacity of beneficial microbes that live in the gut to synthesize a molecule that is the ‘gold standard’ therapeutic strategy for Parkinson’s disease,” said Anumantha Kanthasamy, PhD, Professor and Johnny Isakson Chair. , Georgia Research Alliance Eminent Scholar at the University of Georgia (UGA) in Athens, Georgia. “This next-generation microbial bioengineering technology is designed so that patients with Parkinson’s disease can make their own L-DOPA with microbes in their gut.”

Piyush Padhi, a doctoral student in Kanthasamy’s lab, presented the new research at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics at the Experimental Biology (EB) 2022 meeting, held April 2-5. 2022 in Philadelphia.

Microbiome-based therapeutics for Parkinson's disease

A probiotic has been engineered to endogenously produce L-DOPA from tyrosine using the recombinant genes for 4-hydrophenylacetate 3-monooxygenase and FAD reductase. Live biotherapeutic L-DOPA is pre-activated and administered orally. Testing of the new drug delivery approach reveals steady-state plasma L-DOPA levels and brain dopamine levels in preclinical animal models. Credit: Piyush Padhi, University of Georgia

Dopamine replacement in the form of levodopa L-DOPA tablets taken 3-4 times a day has been used to treat Parkinson’s disease for over six decades. Although treatment reduces the symptoms of the disease, serious motor side effects – called levodopa-induced dyskinesia – begin to develop after about five years of use. This complication is related to the fact that the supply of L-DOPA to the brain is not continuous.

To address this challenge, Kanthasamy’s research team used newly developed synthetic biology and genetic engineering techniques to generate a safe and tolerable probiotic bacterium capable of synthesizing L-DOPA from tyrosine produced by the body.

“After several iterations and refinement of gut microbiome-based drug delivery technology, we have developed a gut-healthy probiotic bacterium that can produce stable levels of L-DOPA in a way that can be highly adjusted to deliver the required dose for each patient,” says Padhi.

Ideally, the treatment would be delivered in an encapsulated pill taken once or twice a day. The dose can be adjusted by pre-activating the cells with rhamnose – a simple sugar that enables bacteria to produce L-DOPA – or by changing the number of bacterial cells delivered in a pill.

Tests of the new drug delivery approach in rodent and dog models have shown that it can achieve consistent levels of L-DOPA in the blood plasma and stable brain dopamine levels without any unwanted fluctuations. The researchers also found that live biotherapy improved motor, cognitive and mood-related tasks in a mouse model of Parkinson’s disease.

“We hope that our continuous, nonpulsatile microbial delivery method for L-DOPA will limit the development and progression of levodopa-induced dyskinesia,” said Kanthasamy, who also directs the Center for Brain and Disease Sciences. neurodegenerative disorders from UGA. “We are currently exploring the use of this approach to provide treatments for other conditions such as Alzheimer’s disease and depression and are in the process of initiating FDA approval for clinical trials of this novel gut microbiome therapeutic technology.

Piyush Padhi will present this research from 10 a.m. to 12 p.m., Sunday, April 3, at Exhibit/Poster Hall AB, Pennsylvania Convention Center (Poster Board Number B182) (abstract) and from 1:31 to 1:44 p.m., Monday April 4 , in room 109 AB (summary). This work will be presented at a virtual press conference from 11:00 a.m. to 11:45 a.m. EDT on Friday, April 1 (RSVP by Thursday, March 31). Contact the media team for more information or to obtain a free press pass to attend the meeting.

Meeting: Experimental Biology 2022

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