Bugs, drugs, and the brain: live biotherapeutics for neurodegenerative diseases

Abstract

Live biotherapeutic products (LBPs) are microorganisms intended to prevent and treat diseases, and there is a growing interest in genetically engineering LBPs to deliver therapeutics to their hosts. LBPs have shown preclinical effectiveness in diagnosing and treating multiple diseases, including in clinical trials. Bacterial LBPs that persist in the gut show potential for more consistent and prolonged drug delivery, which can be especially important for neuromodulatory drugs, whose activity can be highly concentration-dependent. For example, treatment of Parkinson’s disease, a debilitating neurodegenerative disease that affects movement, requires external dopamine supplementation in the form of levodopa (L-DOPA) to improve symptoms. Unfortunately, the effectiveness of L-DOPA wanes as a patient’s tolerance narrows with disease progression. Continuous L-DOPA delivery is needed to maintain motor control in late-stage PD. To determine whether LBPs could be a solution, the probiotic Escherichia coli Nissle 1917 was engineered to produce L-DOPA. Pre-clinical results showed promise, as oral delivery yielded sufficient levels of L-DOPA to improve motor function in both sexes of a mouse model of PD, without the side effects of chemical L-DOPA. Given the safety and efficacy of this approach, we propose that LBPs may yield new treatment options for other neurodegenerative diseases.