Solidus Biosciences, Inc. in partnership with Rensselaer Polytechnic Institute is proposing to address a critical need in chemical safety technology through its proprietary """"""""Transfected Enzyme and Metabolism Chip"""""""" (or TeamChip) for high-throughput analysis of systematic drug candidate and chemical metabolism and toxicology. The TeamChip is being developed to mimic the first-pass metabolism of the human liver and to predict enzyme-specific hepatotoxicity. The effects of metabolism on other cell types will also be demonstrated. Thus, the reactivity of target compounds with individual human metabolic enzymes or combinations of enzymes in the human liver or other organ types can be assessed and quantified at speeds commensurate with predictive human toxicity assessment of early stage drug candidates and environmental chemicals.
The specific aims of this Phase I STTR project are to: 1. Develop efficient methods for transfecting genes into THLE-2 human liver epithelial cell lines and Beas-2B human lung epithelial cell lines encapsulated in 3D alginate matrices as small as 30 nL. 2. Construct recombinant adenoviruses that carry genes for metabolic enzymes from a human liver cDNA library (e.g., CYP450 isoforms including CYP1A2 and CYP3A4) and demonstrate gene transfection on monolayers of THLE-2 and Beas-2B cells using fluorogenic substrates in a 96-well plate. 3. Demonstrate 3D cellular microarrays containing metabolic enzyme-expressing THLE-2 and Beas-2B cells and identify metabolic genes whose differential expression affects the cellular response to chemicals as proof of concept. In vitro technologies that can be used to quickly assess large numbers of compounds for toxicity remain limited. A critical component of safety evaluation is metabolism and toxicology of chemicals (e.g., drug candidates and environmental chemical toxicants), which reflects the susceptibility of chemicals to be metabolized by human metabolic enzymes and the toxicity of parent compounds and their metabolites. Current approaches to chemical safety assessment are costly, time consuming, and use large amounts of compound and large numbers of animals. Thus, there is great potential and opportunity to apply the TeamChip as a safety assessment tool that can be used to evaluate whether and how specific metabolic enzymes contribute to the toxicity of drug candidates and chemical toxicants. This capability may also be used to predict differences among individuals in drug and chemical metabolism and toxicity. 1
The drug discovery process is an investment-intensive, high-risk endeavor that results in low yields of effective and safe drugs;a problem that is confounded by the significant lack of information that exists in predicting the metabolic fate of drug candidates, in general, and in predicting the reactivity of drug candidates in the human body. The proposed Phase I STTR project for the development of Solidus Bioscience's TeamChip technology has significant relevance to public health by providing pharmaceutical researchers with the information needed to predict the in vivo metabolism of drug candidates, and thus help to decide which compounds are brought forward for lead optimization and the ultimate development of better and safer drugs. Furthermore, this research is relevant to the prioritization of industrial and environmental chemicals in terms of their safety and use.
| Yu, Kyeong-Nam; Nadanaciva, Sashi; Rana, Payal et al. (2018) Prediction of metabolism-induced hepatotoxicity on three-dimensional hepatic cell culture and enzyme microarrays. Arch Toxicol 92:1295-1310 |
| Sterner, Eric; Masuko, Sayaka; Li, Guoyun et al. (2014) Fibroblast growth factor-based signaling through synthetic heparan sulfate blocks copolymers studied using high cell density three-dimensional cell printing. J Biol Chem 289:9754-65 |
| Kwon, Seok Joon; Lee, Dong Woo; Shah, Dhiral A et al. (2014) High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening. Nat Commun 5:3739 |
| Paredes, Diana I; Watters, Kyle; Pitman, Derek J et al. (2011) Comparative void-volume analysis of psychrophilic and mesophilic enzymes: Structural bioinformatics of psychrophilic enzymes reveals sources of core flexibility. BMC Struct Biol 11:42 |
