Solidus Biosciences, Inc. in partnership with Rensselaer Polytechnic Institute, will focus on further development, validation, and commercialization of 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 first-pass metabolism of the human liver and to predict enzyme-specific hepatotoxicity. A library of human cells expressing different combinations of metabolic enzymes on the TeamChip will be prepared by transfecting metabolic genes using a viral delivery system into human cells encapsulated in three-dimensional (3D) matrices (as small as 60 nL) arrayed on a plastic chip. 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 /milestones of this Phase II STTR proposal are to: 1. Construct recombinant adenoviruses that carry genes for metabolic enzymes from a human liver cDNA library (e.g., representative CYP450 isoforms and conjugative metabolic enzymes), demonstrate gene transfection on monolayers of Hep3B cells using fluorogenic/luminescent substrates, and measure different levels of adenoviral enzyme expression by Western blot assays. 2. Prepare the TeamChip containing Hep3B cells expressing various combinations of metabolic enzymes and identify metabolic genes whose differential expression affects the cellular response to model compounds. 3. Optimize on-chip cryopreservation protocols for recombinant adenoviruses and transfected Hep3B cells. Demonstrate metabolism-induced toxicity with cryopreserved TeamChips and compare the results with non- frozen counterparts. 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.
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 II STTR project for the development of Solidus Bioscience's TeamChip technology has significant relevance to public health by providing pharmaceutical researchers with in vitro 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. (2017) Prediction of metabolism-induced hepatotoxicity on three-dimensional hepatic cell culture and enzyme microarrays. Arch Toxicol :|
|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|
|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|
|Meli, Luciana; Barbosa, Hélder S C; Hickey, Anne Marie et al. (2014) Three dimensional cellular microarray platform for human neural stem cell differentiation and toxicology. Stem Cell Res 13:36-47|
|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|