Human normal tissue patient-derived organoids for pre-screening GI radiation countermeasure drugs

Columbia University Health Sciences, New York NY

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Exposure to high acute doses of ionizing radiation as a consequence of a radiological or nuclear event can cause illnesses known collectively as acute radiation syndrome (ARS). No medical radiation countermeasure has been approved as yet by the FDA to specifically counteract gastrointestinal (GI) ARS. Radiomitigators efficacy studies cannot be conducted in humans for ethical reasons, thus the FDA requires these tests in well-controlled animal studies. Two concerns however arise; first, the results obtained from animal models do not always translate to humans: For instance, they may not reflect the inter-individual variability in the human response to radiation damage due to factors such as age, sex, and genetic predisposition. Second, in- vivo animal studies are laborious and expensive, and are not generally consistent with screening a large number of drugs or drug variants. Thus, there is a need for alternate pre-screening models which are a) based on normal human GI tissue and b) amenable to high-throughput pre-screening. To fill this gap, our goal is to develop and validate the use of human normal tissue patient-derived organoids (NT-PDOs) established from healthy normal tissue biopsies for pre-screening new candidate GI radiation countermeasures, and to assess the significance of age and sex, in a high-throughput multi-well format. In the context of GI ARS, NT-PDOs are an excellent extracorporeal model for the personalized screening of radiomitigators. They stably replicate the morphological characteristics and physiological functions of the original donor tissue, accurately reproduced the response of the human intestine to known toxic and nontoxic drugs, and when exposed to ionizing radiation, cognate organoids had similar survival dose responses as small and large intestinal crypts in mice. With two interrelated Aims, this proof-of-concept study aims at evaluating the feasibility of using NT-PDOs as proxy of the native organ to test the efficacy/safety of new candidate radiomitigators before advancing to more complex animal studies. To this end, efficacy of the test radiomitigator CBLB502 will be evaluated in organoids derived from the small intestine of individuals of different ages and sex. In Aim 1, effectiveness of the test radiomitigator will be assessed as organoid survival and viability dose-responses. The mode of action of CBLB502 has been well characterized in animal models; the goal is to evaluate whether the drug exerts similar functions in irradiated NT-PDOs. In Aim 2 for both sexes, the sample group identified in Aim 1 with the combination of age, radiation dose, and time of administration of the drug after exposure that shows the biggest effect on survival compared to respective sham-treated controls, will be analyzed using a RNAseq approach coupled with RT-PCR of selected genes of interest. The use of NT-PDOs to pre-screen medical countermeasures in a high-throughput multi-well format can complement the animal in-vivo based strategy for the assessment of radiation countermeasures for GI ARS.