BioFocus on a primary path to screening
primary cells in an attempt to improve pharma productivity,
although first it must persuade the industry that the technique is
reliable.
BioFocus DPI, the service division of Belgian pharma company Galapagos, is extracting cells directly from disease-related tissue in order to find both drugs and targets for drugs, as well as their mechanisms of action. Traditionally, drugs are tested in an artificial cell line that focuses on cloning and producing a single drug target. However, although this has been successful, there is a "growing feeling within the industry that this approach is not enough," according to Dr Iain James, the senior director of biology at BioFocus, who was speaking at the Society for Biomolecular Sciences conference in Montreal last week. "The motivaton for doing this, taking a step back, is the [dwindling] productivity of the pharmaceutical industry over the last 10 years and the perceived lack of delivery of the whole genomics approach," he said in an interview. Although the technology is "is not really mainstream yet", Dr James said: "In my view, it will become one of the important responses to this perceived drop in productivity, which many people think is at least partly due to the relatively simplistic approach of testing against a single target." However, using the cells in this way is a new area for the company and, as with any new technology, Dr James admitted that the company had come up against problems. Although BioFocus is yet to finalise a deal with its first customer for the PrimePath service, the company is working hard to tackle the problems associated with these cell lines and convince pharma companies that the approach is viable. "The approach is slightly ahead of the curve and I think we'll probably have to work a bit hard to convince people that it's something they should do," he said. The key question with primary cells is, are the results reproducible? Dr James said that researchers are concerned because the cells come from donors, and so they are not going to be the same every time, unlike cell lines. "For primary cells, you'll be able to do some simple things that will allow you to reset and recalibrate the cells from donor to donor," he said. Dr James added that, for example, scientists could test a set of reference compounds with each new donor and then refer between donors' results to calibrate the response. Asked why the company is investing in the technology, he said that BioFocus has developed the technology "as a response to an emerging trend in the way people are approaching drug discovery". There are many examples of drugs that act on multiple targets in the body, and many of these drugs are successful in the clinic, he explained. However, in order to understand the full effects of a drug, the challenge is to design more integrated tests that take at least some of the huge biological complexity of humans into account - something Dr James feels is lacking in old-fashioned target centred drug discovery. "The primary cell represents something which is much closer to what is actually happening in the body," he said. In this way, scientists may be able find new targets for potential drugs, predict the side-effects of potential drugs more effectively and even find new uses for old drugs. The technology could also be used to design drugs that work better through greater understanding of how exactly the drug works. The technology is already being used within Galapagos' internal drug discovery programmes, for example to find drug targets. In order to study the protein products of genes, BioFocus utilises virus' covering many different target types (such as GPCRs, ion channels and kinases), while focussing on the so called drugable genome. For example, when suppressing the alpha subunit of Gs, the knock-down of the protein lasted for 10 days, which enables quite complex experiments, according to Dr James. He also said that BioFocus has conducted target finding research using extracted synovial fibroblast cells, which play an important role in cartilage and bone degradation in rheumatoid arthritis. During this work, the scientists uncovered compounds that reduce bone loss from 60 per cent (in controls) to zero. BioFocus' has used the technique to examine the mechanism of action of potential drugs. This is possible as there are multiple targets in the cell, allowing scientists to look at the bigger picture of a cell's response to drug, as opposed to simply how a specific target is regulated. The technology is flexible and has been designed to allow multiple readouts, including ELISA, real time PCR and microscopy. Abbott Laboratories has also used primary cells to examine the mechanism of kinase inhibitors in anticancer drug development. Abbott discovered potent, selective Akt inhibitors that kill renal carcinoma cells but wanted to know if any other kinase pathways interact with Akt. The company achieved this by treating cells with a non-lethal, low dose of the inhibitor A-443654 and then, using small-interfering RNA (siRNA), looked for non-target genes affected by the drug. BioFocus is taking advantage of its new owner's expertise in primary cells and combining this with its own knowledge of small molecule drug screening to develop PrimePath. Galapagos has been using primary cells to find new drug targets "since it started as a company", according to Dr James. "This was one of its signature technologies, using primary cells to find new drug targets," he said. Dr James also revealed that discussions are underway with a third party to begin a screening programme. Such external validation of the technology is crucial to attracting other customers, he said.
