Details

Autor(en) / Beteiligte

• Padhi, Piyush

Titel

Frontiers in Neurotherapeutics: Next-Generation, Precision-Engineered Microbial Solutions for Neurological Disorders

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2024

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Neurochemical imbalances have profound implications for the progression and presentation of neurological disorders, such as Parkinson's Disease (PD), Alzheimer's Disease (AD), and Major Depressive Disorder (MDD). The therapeutic strategies (i.e., small molecule drugs, biologics, peptides) for treating diseases vary depending on the disease's nature, the therapy's mechanism of action, and the physiological context, which may offer unique advantages or face specific limitations. Herein, we present an innovative therapeutic modality that utilizes the transformative potential of the microbiota-gut-brain axis in neurodegenerative disease management. To combat neurological disorders, we developed a genetically engineered live biotherapeutic, specifically a novel L-DOPA-producing strain (LDBL). The premise of this technology involves utilizing modern synthetic biology and genome engineering techniques to endogenously synthesize L-DOPA from tyrosine using the recombinant hpaB/C genes for a continuous, sustained, regulatable, non-pulsatile, systemic delivery of L-DOPA. This report first presents the application of the LDBL, EcNL-DOPA, for PD. The results demonstrate that the sustained delivery of the drug substance maintains therapeutic L-DOPA levels in plasma, increases brain dopamine, and improves motor functions without any adverse side effects in canine and Parkinsonian animal models. We also evaluated the long-term safety and efficacy of LDBL in PD models, addressing the complications associated with traditional L-DOPA therapy. Our findings demonstrate that LDBL can significantly enhance motor and gait functions without exacerbating gastrointestinal dysfunctions or altering the overall microbiome structure, making it a safer and more effective alternative to conventional therapies. Our research delved deeper into the potential of a therapy to address norepinephrine (NE) deficiency in models of AD and PD. Our findings suggest that the therapy can significantly improve cognitive deficits and neuropathological outcomes in pre-clinical models of AD and alleviate motivational deficits and anhedonia in a mouse model of MDD. To achieve success in pre-clinical trials and prepare for the scale-up of first-in-man studies, we optimized LDBL manufacturing and bioprocessing strategies and examined various formulation methods to enhance the viability and therapeutic functionality. Overall, these studies highlight LDBL as a promising candidate system for sustained neuroactive compound delivery aimed at alleviating the burden of these debilitating conditions.