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

Award Number: R00EB035165
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Development of a Gene-Transfer-Resistant and Biocontained Next-Generation Bacterial Host for Controlled Drug Delivery - 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 and chronic disease treatment. The PI 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 aims to overcome these barriers to 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. In the career development (K99) stage of this award, the PI received extensive training in proteomics, the use of animal models, and host-virus interaction analyses from an expert advisory team and achieved the first aim of the project, the construction of a broadly virus-resistant microbial host that prevents transgene release. By building on the mentored stage, in the independent R00 stage of this proposal, the PI will 1) create a tightly biocontained microbial host that utilizes a safe, food-supplement-based genetic biocontainment system, and 2) will combine these technologies into a microbial living therapeutic host and demonstrate 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 chronic autoimmune and metabolic disorders to cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $249,000 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	2/2/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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

Award Number: R00EB035165

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/22/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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