# Microbial Synthesis of Therapeutic Bile Acids for Alzheimer's Disease

> **NIH NIH R42** · METSELEX, INC. · 2024 · $1,280,101

## Abstract

ABSTRACT
This Phase STTR Phase II proposal aims to engineer and scale-up a synthetic metabolic pathway in a microbial
host to produce UDCA and related compounds. Additionally, the UDCA produced from the engineered synthetic
metabolic pathway will be used to synthesize derivatives for testing in our Alzheimer’s Disease cell and animal
models. The proposed work has high intellectual merit for the following reasons: (i) UDCA biosynthesis does
not occur in any organism whose cultivation can be scaled to meet global demand, (ii) UDCA requires a multi-
organism biosynthetic pathway (animal cholic acids converted to UDCA by the gut microbiome) that will have to
be reconstituted in a single cell, and (iii) the anticipated scale and complexity of this engineering effort (combining
more than a dozen genes from four organisms) are on the edge of what is feasible. Technical hurdles involve
the discovery of new enzymes that convert ergosterol to cholesterol (a process known to exist in brine shrimp),
achieving proper localization and enzymatic activity for fifteen recombinant gene products in yeast, and balancing
the expression levels of each gene to support high-titer production of UDCA in yeast. The combined
Metselex/University of Minnesota team will overcome these hurdles using their platform for multi-gene pathway
refactoring and high-throughput DNA assembly and analytical methods. Experience with these tools/approaches
and success in engineering similar synthetic metabolic pathways qualifies this team conduct these studies and
will enable them to accomplish their Phase II goals.

## Key facts

- **NIH application ID:** 10893950
- **Project number:** 5R42AG083665-03
- **Recipient organization:** METSELEX, INC.
- **Principal Investigator:** Gunda I. Georg
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,280,101
- **Award type:** 5
- **Project period:** 2020-06-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893950

## Citation

> US National Institutes of Health, RePORTER application 10893950, Microbial Synthesis of Therapeutic Bile Acids for Alzheimer's Disease (5R42AG083665-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10893950. Licensed CC0.

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