Published online 19 November 2009 | Nature | doi:10.1038/news.2009.1097

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Gene silencing predicted to improve drug manufacturing

Biotech firm hopes to use RNA interference to boost drug yields.

cellsChinese hamster ovary cells: the workhorse of the biological drug market.Nikon MicroscopyU

The burgeoning science of RNA interference (RNAi) — touted as the next frontier in pharmaceutical treatment — is now being directed at increasing the efficiency of drug manufacturing processes.

Alnylam Pharmaceuticals, a biotech firm based in Cambridge, Massachusetts, already uses RNAi in its drug-discovery research. The technique involves using small RNA molecules to reduce the activity of specific genes.

Now, the company plans to use the technology to improve the production of protein-based medicines, monoclonal antibodies, vaccines and other biological drugs, also known as biologics. On 12 November the company announced a new venture, called Alnylam Biotherapeutics, to develop the technology and partner with biopharmaceutical manufacturers interested in using the approach to improve their drug-producing cell cultures.

John Maraganore, Alnylam's chief executive, says that the company has sequenced the genome of Chinese hamster ovary (CHO) cells, the most widely used cell line in the US$100-billion biologicals market. Using the genome, Alnylam has designed small RNAi molecules that can extend the lifespan of the cells — and potentially boost the yield of the drugs they produce.

Silencing two genes in the cell-death pathway, for instance, extended the life of the cells by about 40%; targeting one involved in lactic-acid metabolism boosted lifespan by 60%. "We have already shown that we can harness RNAi technology to alter the cell to live longer and do more of what it needs to do," Maraganore says.

The approach is not without precedent. A handful of researchers, including Zhiwei Song, an engineer at the Bioprocessing Technology Institute in Singapore, have shown that RNAi can more than double the quantities of proteins secreted by CHO cells in the laboratory1. The challenge, says Song, will be to extend the technique to large-scale cultures in bioreactors that can hold tens of thousands of litres of CHO cells.

"A means to enhance the expression of biologics without changing the master cell banks would certainly be of great industry interest," says Derek Ellison, chief operating officer of Eden Biodesign, a contract biopharmaceutical manufacturing company in Liverpool, UK. First, though, Alnylam would have to prove that RNAi doesn't introduce any impurities or alter the quality of the drugs, he says. Companies would also have to redevelop their downstream processing to cope with the increased quantities of product.

Suh-Chin Wu, a cell-culture bioengineer at the National Tsing Hua University in Taiwan who recently wrote a review article2 about using RNAi in CHO cells, doesn't expect many problems with quality or safety. RNAi-based medicines, which are currently in multiple late-stage clinical trials, have not caused any serious side effects in patients. So adding the small RNA molecules to a cell-culture system should not pose any health risks or add any regulatory hurdles, he says.

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Even if the process works, however, the technology might not be profitable, cautions Tillman Gerngross, a biological engineer at Dartmouth College in Hanover, New Hampshire. Manufacturing makes up only a sliver of the total cost of drug production, and "making more stuff cheaper is no longer something that people are willing to pay a lot of money for", he says. Instead, RNAi should be used to improve the quality and potency of biologicals, Gerngross says.

Alynlam is starting to do just that. Maraganore says the company is looking beyond cell viability and working to boost the secretion efficiency of recombinant proteins and to alter various properties of biologicals to make them more active. "It's a broad platform that can be harnessed in many ways," he says. 

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