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Delving into RNAi Screening Solutions

Interview with Devin Leake, Ph.D.

In today’s economic climate, outsourcing to research service providers does not seem like a very intuitive idea.  However, the reality that big pharma currently faces is doing more with less.  As pharmaceutical companies downsize and stabilize, the demand for filling development pipelines continues to grow, a situation made tougher as FDA restrictions on approval criteria tighten.  Outsourcing to service providers, such as the Thermo Fisher Scientific RNAi Discovery and Therapeutic Services group, makes real sense, especially now.  Here, we discuss with Devin Leake, Ph.D., Thermo Fisher Scientific Director of R&D, Genomics what makes outsourcing RNAi and small-molecule screening and microRNA profiling so attractive.

1. What exactly does having fully integrated RNAi service capabilities mean?  What is the benefit to the pharmaceutical industry?

   Effective high-throughput RNAi screening and miRNA profiling experiments require the orchestration of multiple complex technologies. From leading RNAi expertise to assay development, lab instrumentation and automation, Thermo Fisher Scientific has developed a comprehensive platform of reagents, consumables, instrumentation and software.  This level of RNAi biology and chemistry capability, reagent supply and infrastructure are often well beyond reach for most clients and can take years to construct from the ground up. By partnering with Thermo Fisher Scientific’s Services group, however, any client can leverage our integrated solutions to compress timelines and reduce the expense to discovery and validation.  For example, clients benefit from our continued commitment to providing the most specific yet potent Dharmacon siRNA and microRNA research tools on the market today.  Using these reagents in high-throughput screens ensures robust, reproducible data representing the cornerstone of RNAi-based screening methods for target ID and validation, toxicology studies and drug repositioning programs.

2. What are the main advantages of RNAi-based screening approaches over classical small-molecule library screening?

   That’s a great question that often comes up in discussion.  In fact, we see RNAi screening as a wholly complementary approach to classical small-molecule library screening and can hugely augment such a program in moving a drug quickly through the development pipeline.  RNAi is more suited to understanding the roles that specific genes play in both disease mechanisms and treatment regimens for those diseases.  One of the biggest problems in the pharmaceutical industry is that drugs may not specifically target the appropriate mechanisms to induce therapeutic benefit across a broad patient population, so many drugs fail in the clinic for reasons of inefficacy or toxicity.  Genome-wide RNAi screening allows researchers to identify nodes in specific pathways where therapies may have more profound effects.  Characterizing specific gene networks involved in disease and drug mechanisms of action lead to improved therapeutic benefit and therefore aid in repurposing drugs.

3. What innovations does Thermo Fisher Scientific employ in the Dharmacon RNAi Discovery and Therapeutic Services portfolio?

   We offer complete RNAi-based screening solutions to accelerate drug discovery and therapeutic development by utilizing best-in-class RNAi reagents, assay technologies and laboratory automation. The portfolio of RNAi-based services is built on an established and exceedingly well-documented history of innovation in the development of both siRNA and microRNA technologies, which allowed us to provide the first ever siRNA library targeting the entire human genome.   Our services provide clients with access to unmatched scientific expertise and the most advanced reagents and bioinformatics tools in the field of RNAi today.  Taken together, this means rapid generation of meaningful results and expert recommendations to transition screening results into drug target leads.  This type of outsourcing is ideal for those pharmaceutical and biotech companies needing supplemental screening capacity or when internal expertise and infrastructure are not available.

4. Why is it important to incorporate a microRNA functional genomics platform into your overall portfolio of services? What can we learn from such a platform?

   MicroRNAs are emerging as not only key regulators of gene expression in fundamental cellular physiology but also as potential biomarkers in the characterization of normal biological processes as well as the diagnosis and prognosis of disease states.  MicroRNA expression profiling coupled with phenotypic screening, accomplished using libraries of microRNA mimetics and inhibitors, permits the identification and validation of microRNA function in both the pathology of disease and the profiling of responses to therapeutic intervention.  In addition, these neo-biomarkers are poised to create a bridge between pre-clinical observations and clinical efficacy and safety.     

5. With regard to microRNA expression profiling, can you explain the importance of the method? What can we learn from this?

   Characterizing microRNA expression in a given disease state or therapeutic regimen yields a unique molecular fingerprint that is far easier to manage than that of the entire transciptome.  Such a molecular fingerprint has intrinsic diagnostic and prognostic value and can be applied to not only better understand the biologic process of the disease but a drug’s mechanism of action in the treatment of that disease.  Our microRNA profiling platform addresses the need to accurately quantitate levels of microRNA expression in a high-throughput, robust, and sensitive manner. We can profile microRNA expression levels from as little as 30 ng of unfractionated total RNA, which is a significant advantage when working with precious clinical specimens.

6. There has also been a lot of discussion around the use of high-content analysis recently.  How can this be used most beneficially in the context of RNAi-based screens?

   Applications of high-content analysis methods and instrumentation let us examine multiple subcellular events induced by RNAi-based gene silencing in a high-throughput manner.  This allows the researcher to gain a deeper understanding of cellular biology by using a multiparametric readout which provides a wealth of information.  The integration of a high-content analysis platform can represent either a primary or secondary step within the RNAi screening workflow.  This approach not only benefits clients that are focusing on specific drug target mechanisms (e.g. GPCRs, kinases) but also those wanting to stratify hits that are more meaningful to their particular goals.  Thus, having more information from a complex cellular response can quickly help the client to understand how target silencing effects drug efficacy and toxicity as well as provide valuable insight to the mechanism of action.  This information-rich approach is proving extremely fruitful in understanding the complexity of microRNA regulation where many more protein targets are predicted than are truly represented within a particular network.