The University of Georgia has received a USD 1.47 million National Institute on Aging U01 continuation award to advance preclinical development of a genetically engineered bacterial therapeutic designed to deliver L-DOPA continuously to the brain. The approach is aimed at addressing cognitive and neuropsychiatric symptoms of Alzheimer's disease without the side-effect burden associated with conventional dopamine replacement therapy. The grant reflects growing NIA interest in microbiome-based biologics as a route into neurodegenerative disease.
The scientific premise centers on evidence that monoamine neurotransmitter deficits — specifically in dopamine and norepinephrine signaling — contribute to the cognitive and behavioral symptoms that characterize early Alzheimer's disease. Standard oral L-DOPA/carbidopa regimens, while effective at transiently restoring these pathways, produce pulsatile plasma fluctuations linked to dyskinesia, agitation, and other adverse effects with chronic use. The research team, led by Anumantha Gounder Kanthasamy and James Gregory Phillips, has engineered E. coli Nissle 1917 strains to constitutively produce L-DOPA in the gut, aiming to achieve steady-state plasma levels that translate into stable central dopamine and norepinephrine restoration. Proof-of-concept data reported in the abstract indicate gut colonization, plasma L-DOPA levels consistent with clinically effective human concentrations, and improved neurobehavioral outcomes in both rodent and canine Alzheimer's models.
The current funding year supports lead optimization, chronic pharmacokinetic and safety profiling, and pharmacodynamic efficacy studies in transgenic rodent models, with the most effective candidate to be evaluated in canine dementia models — a species considered a more translatable model for cognitive aging than rodents alone.
Current FDA-approved Alzheimer's therapies, including cholinesterase inhibitors and the glutamate modulator memantine, address neither dopaminergic nor noradrenergic deficits and have demonstrated limited efficacy against neuropsychiatric symptoms. Lecanemab (Leqembi) and donanemab target amyloid pathology in early disease but do not directly address monoamine circuit dysfunction. The live biotherapeutic approach being developed here occupies a distinct mechanistic space, though it remains at the preclinical stage and faces a substantial translational gap before clinical evaluation.