Sistemic’s original broad-spectrum patent covered miRNA responses to four classes of cancer drugs—HDAC inhibitors, statins, antimetabolites, and inhibitors of DNA replication. The company screened two compounds from each class, such as mevastatin in HeLa cells, then extracted miRNA profiles. Different drug classes generate miRNAs that cluster together and describe phenotypes and biological activity. The miRNA expression profile gives a fingerprint of the cell system.
Sistemic calls its key miRNAs kmiRs. Certain drug classes produce kmiRs specific to biological pathways, such as lipid metabolism for statins. Sistemic researchers discovered that some kmiRs identified for mevastatin are involved in DNA repair and cell-cycle control as well as lipid metabolism. This explains why mevastatin works well as an oncology drug. “So you can use miRNA profiling to reposition drugs,” says Dr. Hillier.
Sistemic built a knowledgebase, or database, of kmiRs that represent different drug classes involved in cancer and inflammation, and metabolic and cardiovascular disease. The current oncology platform, for example, contains eight major drug classes with five or more representatives of each class.
The company’s platform technology, SistemRNA™, is based on this growing knowledgebase. It profiles miRNA expression and analyzes changes produced when a cell is perturbed, such as by a drug. SistemRNA captures the dynamic response of all cellular pathways and their interactions. miRNA profiles can be used to elucidate previously unknown mechanisms of action, speed lead candidate selection, sensitively measure time and concentration effects, and identify on/off target effects during drug discovery of novel targets.
The company first used SistemRNA to screen compounds and position new drug compounds or reposition known drugs for better clinical outcomes. Their services evolved to help clients determine the mechanism of action of drugs that proved effective in animal models.
kmiRs represent biological changes, such as enzymes that are up- or downregulated or metabolites produced in response to chemical compounds. “Clients want biomarkers like enzyme changes because they suggest the involvement of a pathway that can be validated,” explains Dr. Hillier. Because such findings do not always correspond with animal data, time is not wasted pursuing unprofitable leads.
kmiRs are ideal for toxicology screening, too, according to Dr. Hillier. Sistemic has miRNA profiles of drugs with proven toxicity problems, such as Vioxx and Avandia. Its assays can measure both the efficacy and safety of drug candidates and distinguish between the chemistries of similar drugs, such as rosiglitazone and glitazone. “We believe our platform is the first one that can do this simultaneously,” Dr. Hillier notes.
Sistemic researchers recently released a new platform, SistemQC™, to monitor small changes in cell cultures, such as stem cells or CHO, BHK, or HEK-293 cell lines used for large-scale biomanufacturing. Genetic drift causes undesirable phenotypic changes in cell lines. In stem cells, small changes can trigger uncontrolled differentiation.
“As stem cell therapies enter the clinic and potential market, there is a huge unmet need for reliable, information-rich QC methods to monitor cells easily and effectively within current workflow processes,” reports Dr. Hillier. Cell changes in bioreactors can slow production or reduce yields of biotherapeutics.
“Biomanufacturing is under pressure to speed up and it takes a long time to recover when a cell line goes down.”
Sistemic hopes to incorporate SistemQC technology into products that other companies sell to monitor cell-line changes, similar to the many brands of computers that run on Intel microprocessors.