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Mixed Messages for RNAi

By Al Doig

February 1, 2011 | Insights | Outlook |  In the late 1990’s, a gene regulatory mechanism known as RNA interference (RNAi) was demonstrated that involved the inhibition of specific gene expression by small, double-stranded RNAs. This RNA silencing could be caused by introducing a small synthetic RNA into a cell or organism that has the specific complementary sequence for the expression controller on the target gene.

RNAi was recognized with the award of the 2006 Nobel Prize in Physiology or Medicine to Craig Mello and Andrew Fire a mere eight years after their discovery, and the technology has since become an indispensable research tool in determining gene function, in analyzing pathways, and in drug target validation.

More recently, a related role was demonstrated for micro-RNAs (miRNAs), a class of naturally occurring small RNAs also involved in gene regulation. Pathways for production of miRNAs, as well as mechanisms of miRNA action, are related to mechanisms for RNAi. These discoveries have contributed to an intense interest in applying this biology to the development of oligonucleotide drugs by building off of the platforms established for antisense drug development. Driving this interest is the potential for RNAi and miRNA to address drug targets that are considered to be undruggable.

“Small molecules and biologics are capable of targeting only about 20% of the gene products from our genome,” says James Thompson, VP pharmaceutical development at Quark Pharmaceuticals. “Eighty percent of the genes in our genome aren’t pharmacologically tractable, or druggable, by either small molecules or biologics. RNAi/miRNAs can target all of them. So we open up a whole new, large number of potential therapeutic targets. That’s...why pharma companies are interested.”

In Good Company

Leading companies in the therapeutic RNAi field include Alnylam, Tekmira, Sirna/Merck, RXi, Calando, Silence, Quark, and Dicerna. In miRNA therapeutic development the leading companies include Regulus, Santaris, and miRagen. In the diagnostics area, miRNA-based products are under development by Rosetta Genomics and Asuragen. Large pharma companies, in addition to Merck and Pfizer, are involved either directly or through ventures with in start-up companies.

The indications for RNAi/miRNA candidates in clinical trials include respiratory syncytial virus lung infection, wet age-related and diabetic macular degeneration, hepatocellular carcinoma, amyloidosis, acute kidney injury, metastatic melanoma, dyslipidemia, and nonarteritic ischemic optic neuropathy (NAION).

Nevertheless, there are signs of growing pharma and investor impatience with the pace and prospects of RNAi research. Alnylam, a public biotech founded in 2002, is generally considered to be the leader in the therapeutic RNAi field. But despite healthy funding, a sizable IP estate, and a Scientific Advisory Board (SAB) consisting of the Who’s Who of RNAi research, the value of its stock has been in decline.

Last September, Alnylam and Novartis announced an end to their partnership, followed by Alnylam’s cutting about 25 percent of its workforce. Then, in November, Roche announced its decision to pull out of RNAi altogether as part of a global restructuring effort. Although these announcements were rather high profile events, Alnylam and others continue to benefit from partnerships with big pharma companies. The decisions by Novartis and Roche may reflect more on the reallocation of resources at a time of broad restructuring within the pharma industry rather than on the potential of RNAi/miRNA therapeutics.

The first true RNAi-based drugs, which are likely to be locally delivered or liver-targeting drugs, are several years away from approval, as the most advanced candidates have only progressed to Phase II clinical trials to date. However, as an early stage technology, there are some notable parallels with the evolution of monoclonal antibody (MAb) field.

It was a 1975 publication describing the technology for generating MAbs, for which the authors received a 1984 Nobel Prize, that ignited interest in the possibility of MAb therapeutics. In the 1970s and 1980s, MAb technology represented great science, and biotechnology and pharmaceutical companies were excited at the prospect of developing MAb drugs. However, the development of MAb-based drugs lagged far behind the science.

The first MAb drug, Johnson & Johnson’s Orthoclone OKT3, was approved in 1986, albeit with limited applicability. Interestingly, there were no other approved MAb drugs until 1994 and the “avalanche” of MAb drug approvals didn’t begin until 1997. “Today we just take this technology platform for granted, but in the early days the prospects for monoclonal antibodies were even more controversial than RNAi is,” observes Arthur Krieg, chief scientific officer of Pfizer’s Oligonucleotide Therapeutics Unit.

Al Doig is general manager, Insight Pharma Reports. He can be reached at

Further reading: The field is reviewed in Insight Pharma Reports’ RNAi Therapeutics: Second-Generation Candidates Build Momentum Report. June 2010.

This article also appeared in the January-February 2011 issue of Bio-IT World Magazine. Subscriptions are free for qualifying individuals. Apply today.
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