April 2011

RNAi therapeutics run interference

RNA interference is getting the axe at major pharmaceutical companies. Is it too soon?

In February of 2008, the future looked bright for Arthur Krieg and a little technology known as RNA interference. Krieg had just joined Pfizer after the pharmaceutical giant acquired Coley Pharmaceuticals, a company he had cofounded in 1997 and where he had served as the chief scientific officer and executive vice president of research and development. Based on his extensive experience in developing oligodeoxynucleotides, Pfizer asked Krieg to head up a new division devoted solely to RNAi.

"I had to tell the group that we were being shut down. All the sites associated with our RNAi program were being closed, and all positions were being eliminated."

This biological phenomenon, which knocks down or dramatically lowers the protein output of selected genes by inserting a piece of double-stranded RNA into cells, was making leaps and bounds in the lab. Pfizer and many other big pharma companies saw this new technology as the wave of the future – a new way to target practically any gene that has a known sequence.

But this February – nearly three years to the day after he started his new position – Krieg stood in front of the 100-member group that Pfizer had hired to run its RNAi program to make a terrible announcement.

“I had to tell the group that we were being shut down. All the sites associated with our RNAi program were being closed, and all positions were being eliminated,” he says.

What happened in those three intervening years? Whatever it was had also happened to other big pharma companies who invested in RNAi. Roche, Novartis, and Abbott Labs recently terminated their RNAi programs and severed their ties with biotech partners who were helping to develop the technology, sending shock waves through the field.

But while RNAi is getting the axe at big pharma, the technology has continued to march quietly forward at smaller biotech companies and academic labs. Animal studies recently have shown that RNAi could hold incredible promise for treating HIV, and human studies for cancers and other diseases are moving ahead into Phase 1 and 2 clinical trials. Could big pharma have pulled the plug before RNAi hit the big time?

Pulling back

RNAi still is an incredibly nascent technology. It only was discovered in the late 1990s, detailed for the first time in a seminal 1998 Nature paper by Andrew Fire and Craig Mello. There, the two scientists wrote about a strange phenomenon whereby double-stranded RNA injected into C. elegans had the power to potently silence genes. Since then, researchers have discovered that this concept also works for all living things – plants, insects and, eventually, humans.

The ability to silence any gene in the body would prove to be an incredible boon to research. No longer would scientists patiently have to wait a year or longer to make knockout mice to study gene function – with RNAi, the knockout could happen instantly. Additionally, trying to decipher the functions of genes essential to life wouldn’t necessarily have to happen at the embryonic stage, before organisms bit the dust early on. Rather, researchers could knock these down later in life and see what happens.

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