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Development of a FRET based Bile Salt Export Pump Inhibition Liposomal Assay

Award Number: R44GM110858
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2015
PERIOD OF PERFORMANCE END DATE: 09/14/2022

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Development of a FRET based Bile Salt Export Pump Inhibition Liposomal Assay - A successful Phase I forms the basis for this Phase II proposal. The goal of Phase II is to bring the Fluorosome-trans- bsep assay to commercialization, providing a fully validated high-throughput solution for drug-induced BSEP transporter inhibition studies to drug development groups worldwide. Our ultimate goal is to commercialize a complete suite of assay reagents for all FDA and EMA mandated transporters, enabling the pharmaceutical industry to efficiently evaluate the suitability of drug candidates for continued development. The “Fluorosome-trans-bsep” reagent will be one of this suite of reagents. We were able to successfully accomplish all the proof-of-principle goals of our Phase I proposal. In brief, we were able to: 1) produce purified human BSEP, 2) reconstitute the BSEP transporter in a functional form into lipid bilayers and confirm its ATPase activity, 3) prepare Fluorosome-trans-bsep by encapsulating a sensor in the interior of the BSEP proteoliposomes, 4) demonstrate BSEP’s transporter function in the resulting Fluorosome-trans-bsep construct; 6) demonstrate the ability of Fluorosome-trans-bsep to detect the active transport of test substrate; and 7) demonstrate that the assay is sensitive to known inhibitors of BSEP. We have made significant advances over what was proposed in Phase I. We have established protocols for production of purified and reconstituted BSEP in-house thereby circumventing any reliance on an external vendor. Secondly, we have purified a Bile Acid Sensor that responds directly to bile acid, the physiological substrate of BSEP. Thus, ATP-driven bile acid transport mediated by BSEP and inhibition of this BSEP function by drugs can be directly measured in the Fluorosome-trans-bsep construct. For Phase II, we will bring the Fluorosome-trans-bsep assay to a commercial stage. When successful, this assay will be the first off-the-shelf high throughput assay available to drug developers that is unambiguously specific for the BSEP transporter inhibition. The assay uses small amounts of test material, is simple to use and requires only a standard injecting multiwell fluorescence plate reader, which generates real time data in under a minute. To bring this assay to commercialization, we propose: 1) the development of various in-house processes/technologies that enable the large scale production of purified BSEP and Bile Acid Sensor proteins and their successful incorporation into our Flurosome-trans-bsep reagent; 2) the necessary extensive validation of the assay using drugs known to interact with BSEP; 3) establishment of rigorous quality control methods required for reagent manufacture and storage; and 4) finally, the implementation of an Early Adopter Program. The Fluorosome-trans-bsep assay will be poised to enter the market as a highly competitive and useful product. This will greatly facilitate us in bringing our other two Fluorosome assays, those for the human P-glycoprotein and Breast Cancer Resistance Protein, into the marketplace.


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: 2023 ( Subtotal = $0 )
2023	2020	TFC BIOSCIENCES, INC.	101 ACCESS ROAD UNIT 201	NORWOOD	MA	02062	NORFOLK	USA	Biomedical Research and Research Training	000	3	6/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $684,797 )
2020	2020	TFC BIOSCIENCES, INC.	101 ACCESS ROAD UNIT 201	NORWOOD	MA	02062	NORFOLK	USA	Biomedical Research and Research Training	000	3	9/10/2020	NON-COMPETING CONTINUATION	$684,797
														Subtotal = $684,797

Issue Date FY: 2019 ( Subtotal = $710,211 )
2019	2019	TFC BIOSCIENCES, INC.	101 ACCESS ROAD UNIT 201	NORWOOD	MA	02062	NORFOLK	USA	Biomedical Research and Research Training	000	2	9/11/2019	COMPETING CONTINUATION	$710,211
														Subtotal = $710,211

Grand Total All Awards = $1,395,008

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Development of a FRET based Bile Salt Export Pump Inhibition Liposomal Assay

Award Number: R44GM110858

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2015

PERIOD OF PERFORMANCE END DATE: 09/14/2022

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