# Development of a Gene-Transfer-Resistant and Biocontained Next-Generation Bacterial Host for Controlled Drug Delivery

> **NIH NIH K99** · HARVARD MEDICAL SCHOOL · 2024 · $120,498

## Abstract

Project Summary/Abstract. Synthetic biology transformed our ability to rationally reprogram cells and use
such engineered living organisms, instead of small molecule drugs or biologics, as novel therapeutics.
However, living therapeutics proliferate and release their engineered genetic information into natural biomes
through horizontal gene transfer. Consequently, the widespread use of engineered living therapeutics
necessitates the development of efficient biocontainment technologies that not only prevent the unwanted
proliferation of cells but also eliminate the release of genetic information (transgenes) from such genetically
modified organisms (GMOs).
 The overarching goal of my proposal is to solve these challenges and develop the first microbial host
for programmable drug delivery that simultaneously provides tight biocontainment, prevents transgene release
─ horizontal gene transfer ─ into wild organisms, and offers increased stability for long-term drug production.
The PI recently demonstrated that engineering the genetic code of living cells provides a tight, potentially
unbreakable genetic firewall that eliminates horizontal gene transfer and links the survival of cells to the
presence of small molecules not available without human supplementation. However, these early experiments
also revealed significant barriers in front of the clinical translation of this technology. This project will overcome
these barriers and generate a bacterial host for controlled drug production that prevents transgene release and
viral predation while offering strict biocontainment without escape from human therapeutic doses. This goal will
be achieved through 3 specific aims: 1) The construction of a broadly virus-resistant microbial host that
prevents transgene release by generating and characterizing multiple artificial genetic codes. 2) The creation
of a tightly biocontained microbial host that utilizes a safe, food-supplement-based genetic biocontainment
system. Finally, in Aim 3, the PI will combine these developments into a microbial living therapeutic host and
demonstrate in a proof-of-concept experiment that this host enables stable, long-term therapeutic enzyme
production inside the GI tract.
 In summary, this work will create a technology and microbial host capable of addressing a wide range
of unmet needs in therapeutics development and de-risk the use of microbial GMOs for clinical translation, with
potentially broad impact on diseases ranging from autoimmune and metabolic disorders to cancer. The
proposed research and career development plan will be conducted in the lab of Dr. George M. Church at
Harvard Medical School, and the PI, Dr. Akos Nyerges, will receive extensive training in proteomics, the use of
animal models, and host-virus interaction analyses during the K99 phase from an expert advisory team. The
career development plan and the outstanding scientific environment of Harvard will enable the PI to achieve
the scientific goals of this ...

## Key facts

- **NIH application ID:** 10933456
- **Project number:** 5K99EB035165-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Akos Nyerges
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $120,498
- **Award type:** 5
- **Project period:** 2023-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933456

## Citation

> US National Institutes of Health, RePORTER application 10933456, Development of a Gene-Transfer-Resistant and Biocontained Next-Generation Bacterial Host for Controlled Drug Delivery (5K99EB035165-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10933456. Licensed CC0.

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