Planar culture of gastrointestinal stem cells for screening pharmaceuticals for adverse event risk

Ended Project Grant Awarded Last action

Award ID
R43TR004230
Recipient
Awarding agency
Obligated
$513,148

Award facts

Completion date
Place of performance
Research Triangle Park, Durham, NC, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
GI side effects, such as ulcers and diarrhea, represent the most common source of adverse events for pharmaceuticals. GI stem cells are responsible for repairing and replenishing GI epithelium, and pharmaceutical inhibition of these functions likely contribute to adverse event risk. Currently there are no high-throughput and cost-effective means of screening candidate therapeutics for effects on GI stem cells. Animal models are fraught with confounds (e.g., rats generally do not exhibit diarrhea until death is imminent) and current in vitro models like the caco-2 tumor cell line do not include a normal stem cell population. While 3D-organoid cultures have a stem cell component, access to the apical aspect of the monolayer for compound exposure is not possible without low-throughput microinjection. Altis biosystems, INC. Has developed a proprietary culture platform, repligut® planar, enabling primary human GI cells to form an epithelium for drug screening. In preliminary efforts, we initiated development of a GI stem cell-specific platform called repligut® stemscreen to address the unmet need for high-throughput, cost-effective GI stem cell screening, including a range of assays to measure properties that might lead to adverse events. These include assays for proliferation using s-phase staining and assessing downstream differentiation and ability to establish barrier function via non-destructive transepithelial electric resistance (teer) analysis. A panel of pharmaceutical agents associated with clinically adverse GI side effects, tested in a classic EDU assay using stemscreen planar cultures, demonstrated dose-dependent inhibition of stem cell proliferation and prevented stem cell differentiation into a mature epithelium with barrier function. During phase i we will: 1) characterize monolayer proliferation properties of donor cells in the altis biobank(initially transverse colon stem cells will be evaluated, with other regions tested in phase II) from three donors and 2) test a selection of therapeutic agents with known GI adverse event risks for effects on stem cell proliferation, impacting differentiation and the formation of a functional epithelial barrier (indexed as teer). Demonstrating that the stemscreen platform provides an in vitro screening tool capable of predicting a drug's risk for GI adverse events in phase i will enable deeper characterization of stemness, stem cells from other GI regions (e.g., ascending and descending colon; small intestine regions including jejunum, etc.), and stem cell phenotypes. In phase 2, we plan externally validate the platform in collaboration with leading industry laboratories prior to commercial launch.

Transactions

Action Obligated Date
Amendment $0
Amendment $256,574
Original award $256,574

Quick answers

Who received award R43TR004230?

R43TR004230 was awarded to Altis Biosystems, Inc. by National Center for Advancing Translational Sciences (National Institutes of Health) on July 1, 2022.

How much is award R43TR004230 worth?

$513,148 has been obligated on R43TR004230.

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