# In Vitro Toxicity Testing at Massive Scale in Diverse Primary Human Cells

> **NIH NIH R44** · CORAL GENOMICS, INC. · 2021 · $811,373

## Abstract

PROJECT SUMMARY—Coral Genomics is combining whole genome sequencing and RNA profiling in cell-
based functional assays to predict human variation in the metabolism and toxicity of compounds encountered in
therapeutic and environmental exposures. RNA profiling before and after exposure provides a high-dimensional
representation of changes in cell function, and the use of rapid, cost-effective profiling could enable toxicity
testing in large, diverse panels of human cells. Thus, to address the need for toxicity testing that better reflects
the genetic diversity of human populations, Coral developed innovative approaches to reduce the cost and
increase the speed of high-throughput sequencing assays. In a successful Phase I SBIR (R43 HG010445), Coral
established protocols for cost-effective sample multiplexing for rapid shallow sequencing of samples, developed
a re-indexing workflow to pool samples into a single sequencing run, and combined streamlined sequencing
solutions with novel functional assays and algorithms to improve the performance of polygenic risk scores (PRS).
In a collaboration with the US Food and Drug Administration (FDA), Coral applied these techniques to predict
patient-specific hepatocyte response profiles to acetaminophen (N = 200) and found significant interindividual
variability in toxicity. Importantly, the findings show that a patient’s genotype predicts a significant portion (AUC
= 0.85) of the interindividual variation, indicating the approach is sensitive to genetic diversity. Preliminary
findings indicate Coral’s approach may be a sensitive means for identifying differences in toxic responses to
compounds across diverse populations. Further development and testing across multiple compounds in a
large, diverse sample has the potential to provide a scalable, high-throughput platform for effective
toxicity testing that is more representative of the diversity of human responses. Coral proposes a Direct
to Phase II SBIR in response to NIEHS’s RFA-ES-20-208 to evaluate these methods in three cell models and
advance at least one model to full-scale testing with 250 patient samples and 100 compounds with known toxicity
profiles. Aim 1. Characterize the interindividual variability of RNA profile shifts in three human cell models (i.e.,
immune, hepatocyte, and embryoid body) exposed to ten compounds with known toxicity profiles. Select
Milestones: 1) 4,500 response profiles; 2) Statistical significance of intraindividual variability vs. interindividual
variability (p<0.001); 3) ≥ 50% of differentially expressed genes associated with exposure observable with < 1
million reads; 4) R2 > 0.3 for FAERS profile and AUC > 0.85 for Tox21 dataset. Aim 2. Using the most predictive
cell model, characterize interindividual variability of sublethal cytotoxic responses to 100 compounds with known
toxicity profiles to develop a robust model for predicting systemic toxicity. Select Milestones: 1) 75,000 response
profiles; 2) Identification of ≥ 5 ...

## Key facts

- **NIH application ID:** 10112070
- **Project number:** 1R44ES032515-01
- **Recipient organization:** CORAL GENOMICS, INC.
- **Principal Investigator:** Atray Dixit
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $811,373
- **Award type:** 1
- **Project period:** 2021-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112070

## Citation

> US National Institutes of Health, RePORTER application 10112070, In Vitro Toxicity Testing at Massive Scale in Diverse Primary Human Cells (1R44ES032515-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10112070. Licensed CC0.

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