# Evaluation of In Vivo Efficacy of a Novel Microbial Therapy to Treat Cognitive Deficits in Alzheimers disease

> **NIH NIH R41** · PROBIOME THERAPEUTICS, INC. · 2021 · $254,063

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s disease (AD) is a leading cause of dementia, yet no effective therapeutic intervention is available
for those in prodromal and early stages of AD. Restoration of functional and cognitive resilience in early disease
stages is especially beneficial in many aspects as it could substantially extend the period of quality of life and
delay the clinical onset of AD. In search of therapeutic targets for early disease stages, recent studies uncover
a significant loss of TH+ neurons in locus coeruleus (LC) in patients with MCI and very early stages of AD. These
neurons project to the hippocampus, where monoamine neurotransmitters, such as dopamine (DA) and
norepinephrine (NE), modulate synaptic plasticity and neuronal functions relevant to memory and cognition.
Thus, restoration of DA and NE levels in the hippocampus could retain cognitive resilience during early stages
of AD. L-DOPA is a brain penetrating precursor drug for DA to treat Parkinson’s disease. Its therapeutic potency
on AD has not been well investigated in humans in part due to lack of understanding in the pathological
involvement of DA and NE in AD and development of neurobehavioral side-effects for frequent and long-term
use. We, therefore, propose to comprehensively evaluate the therapeutic efficacy of L-DOPA by a novel method
of administration in the mouse model recapitulating early stage of AD phenotypes. Unlike the traditional oral
administration of L-DOPA multiple times a day, which results in fluctuation of L-DOPA in plasma and induces
toxicity, we will give engineered commensal bacteria that produce L-DOPA (EcNrhaL-DOPA) in a sustained and non-
pulsatile manner. Single administration of EcNrhaL-DOPA transiently resides in the gut for a couple of days and
supply L-DOPA without disrupting the gut microbiota. This approach could effectively mitigate fluctuation-
mediated side-effects and L-DOPA toxicity and maximize its therapeutic effects to restore brain DA and NE
levels. As a first step towards evaluating its therapeutic benefits in the relevant AD mouse model, we propose
to optimize the treatment regimen and dosage of EcNrhaL-DOPA administration in APP-KI and wildtype mice and to
evaluate pharmacokinetics and any adverse toxicological effects in this application. The overall impact and
translational significance of this proposed study are extremely high as this approach could not only work
complementally with currently available drugs to treat AD but also significantly slow the progression of AD
phenotypes from early stages to prevent conversion to full spectrum of AD. This novel technology is covered
under USPTO Application # 20190262298, titled “L-DOPA microbiome therapy”.

## Key facts

- **NIH application ID:** 10325228
- **Project number:** 1R41AG074777-01
- **Recipient organization:** PROBIOME THERAPEUTICS, INC.
- **Principal Investigator:** Bhavani Kasibhatla
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,063
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10325228

## Citation

> US National Institutes of Health, RePORTER application 10325228, Evaluation of In Vivo Efficacy of a Novel Microbial Therapy to Treat Cognitive Deficits in Alzheimers disease (1R41AG074777-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10325228. Licensed CC0.

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