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Establishing the feasibility of editing the human gut microbiome

Award Number: R01AT011117
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Establishing the feasibility of editing the human gut microbiome - PROJECT SUMMARY Definitive links between the remarkable inter-individual genotypic variation in the human microbiome and disease are still limited due to the lack of generalizable methods to precisely remove microbial genes from complex microbial communities in situ. Not only would such a technology help transform the microbiome field from a descriptive to a mechanistic discipline, but it would also have immediate clinical applications. The goal of this Focused Technology Research and Development (PAR-19-253) application is to establish a generalizable toolkit to program the endogenous CRISPR-Cas systems in human gut bacteria to knockout genes of interest with unprecedented precision. CRISPR-Cas is a bacterial immune system, composed of RNA-guided nucleases, that protect the cell against bacteriophage and other foreign DNA. Endogenous CRISPR-Cas systems can be programmed to target their own genomic DNA using custom guide RNAs (gRNAs) homologous to a gene of interest. As an initial proof-of-principle we will target a single gut bacterial gene that we discovered is responsible for the inactivation of the cardiac drug digoxin, but if successful this approach could be readily extended to the numerous bacterial species that have now been implicated in host physiology and the predisposition to and treatment of disease. We will pursue the following Specific Aims: (Aim I) the functional validation of a novel CRISPR-Cas system in Eggerthella lenta, a prevalent gut Actinobacterium with multiple links to metabolism and microbial pathogenesis; (Aim II) the isolation and rebooting of bacteriophages that infect human gut bacteria; and (Aim III) the engineering of bacteriophage to program an endogenous gut bacterial CRISPR-Cas system. Our long-term goal is to establish the first modular tools for engineering the gut microbiome to delete one gene, combinations of genes, or even entire metabolic pathways. Importantly, by focusing on endogenous CRISPR-Cas systems, we anticipate that along the way we will uncover basic insights into the diversity, regulation, and function of these systems, with broad implications for our understanding of the complex interactions between bacteriophages, their bacterial hosts, and their shared mammalian habitat. While our early results provide support for feasibility, this high-risk, high- reward technology development plan would have broad implications for the study of microbial communities and host-microbiome interactions while bringing the promise of microbiome-based therapeutics within reach.


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: 2025 ( Subtotal = $0 )
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Research and Training in Complementary and Integrative Health	000	4	8/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $403,750 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research and Training in Complementary and Integrative Health	000	4	5/9/2023	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2022 ( Subtotal = $403,750 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research and Training in Complementary and Integrative Health	000	3	5/13/2022	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2021 ( Subtotal = $403,750 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research and Training in Complementary and Integrative Health	000	2	7/8/2021	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2020 ( Subtotal = $403,750 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Research and Training in Complementary and Integrative Health	000	1	7/23/2020	NEW	$403,750
														Subtotal = $403,750

Grand Total All Awards = $1,615,000

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Establishing the feasibility of editing the human gut microbiome

Award Number: R01AT011117

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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