November 15, 2010 (Vol. 30, No. 20)

Sistemic Finds Its Own Niche by Working with the Technique as a Cellular Master Switch

Most biotechnology startups are built around a technology platform invented in a university laboratory or as a spinoff of another company. Chris Hillier, Ph.D., however, founded Sistemic in 2008 to fill an unmet market need and he created the miRNA technology that drives the company.

In 2007, many companies were focused on RNA interference (RNAi), and the marketplace was saturated with RNAi-based startups. “But no one was looking at miRNA, and we saw a market opportunity,” says Dr. Hillier, CEO of Sistemic, headquartered in Glasgow, Scotland, with an office in Boston, MA.

Dr. Hillier and his co-founders searched intellectual property filings for half a year to find a unique niche for miRNA. They found therapeutic and diagnostic applications, but no one was designing in vitro tools based on miRNA. Dr. Hillier, a pharmacologist, went to work in the laboratory and discovered that miRNAs are highly discriminating biomarkers that describe how cells respond to their environment. He calls miRNA “a control structure inside cells that acts like a cellular master switch.”

miRNA profiles are a reliable indicator of complex cellular activity and a sentinel marker of pathways affected. Compared to historic genomic and transcriptome biomarkers, which require bioinformatics to analyze very large datasets, as few as a 100 miRNAs can describe cellular responses. miRNAs are cell and tissue specific as well.

Following Sistemic’s analytical processes, identified kmiRs are further filtered through a visualization tool with the ability to further separate datasets. Shown here is an amalgam of three datasets (three treatments) superimposed, then filtered for biomarker kmiRs. The image shows that kmiR-4 provides the best discriminatory biomarker for this particular study.

kmiRs Knowledgebase

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.

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