Ride For Life: Killing RNA might help ALS

How do you find an effective hit man? It's a dilemma biologists have been struggling with for more than a decade now, looking for brutish molecules that can whack diseases before diseases whack you. Specifically, what they want is a way to hack up, or "cleave," the RNA that carries the messages that will give you diabetes, Parkinson's, Lou Gehrig's disease, or any number of other undesirable conditions.

This is one of those rare cases when killing the messenger -- the RNA inside your cells that bears the blueprints for disease -- is actually a very smart thing to do. But unfortunately, the first two approaches biologists have tried to bump off this messenger RNA, known as antisense technology and ribozymes, haven't worked very well -- and several of the earliest drugs based on these two approaches have failed in clinical trials.

A third approach, called RNA interference, could turn out to be the right hit man for the job. It was only five years ago that Craig Mello, a reseacher at the University of Massachusetts, and a colleague at the Carnegie Institution named Andrew Fire, demonstrated how RNA interference worked in worms. And it was just two years ago that RNA interference, usually abbreviated as RNAi, was shown to work safely in mammals.

But already, a cluster of companies are working to develop drugs based on RNAi. Several of them are either headquartered in Massachusetts or funded by local venture capitalists. There's talk of Mello and Fire receiving a Nobel Prize for their work, and RNA interference has been named one of the "breakthroughs of the year" by Science Magazine for two years running, the scientific world's equivalent of winning back-to-back Super Bowls.

The far-off, sci-fi promise of RNAi is that it might one day be used to head off a genetic disease before the first symptom appears, based on an analysis of your predisposition to certain diseases.

But much sooner, perhaps within five to 10 years, drugs based on RNAi could be on the market, injected directly into an organ or into the bloodstream to slow the growth of tumors or or fight viruses like HIV or hepatitis C.

Two companies, Cambridge-based Alnylam Pharmaceuticals and Sirna Therapeutics of Boulder, Colo., have each raised more than $50 million to pursue drugs based on RNAi. Alnylam's funding came from Polaris Venture Partners, Atlas Venture, and Merck & Co., among others.

Sirna Therapeutics, a publicly held company once known as Ribozyme Pharmaceuticals, got its money from local VC firms Oxford Bioscience Partners and Techno Venture Management. (Ribozymes are a kind of enzyme that can also cleave messenger RNA.) The company had been developing and testing drugs based on ribozymes -- unsuccessfully -- but changed its focus to RNAi with the infusion of cash. This amounted to a total restart of the company. (The company's new name, Sirna, refers to "small interfering RNA," the type of double-stranded RNA molecule both Sirna and Alnylam are trying to design to serve as a hit man.)

A third company, Worcester-based Araios Inc., is working toward RNAi-based drugs for obesity, diabetes, and Lou Gehrig's disease. Araios is a subsidiary of CytRx Corp., a publicly held Los Angeles company. A fourth RNAi company, Natick-based Sequitur Inc., was purchased last month by a California acquirer -- evidence of the high level of interest in the RNA interference approach.

"We've seen data that shows that 2003 was the first year that there were more FDA approvals of biotech drugs than traditional pharmaceuticals," says John Maraganore, the chief executive of Alnylam. RNA interference, he continues, "has the potential to be the next major product platform in biotechnology, after recombinant proteins and monoclonal antibodies."

One of Alnylam's founders is Phil Sharp, the Nobel laureate and MIT prof who cofounded Biogen in 1978. Alnylam also counts Rockefeller University researcher Thomas Tuschl as an adviser -- whose name also seems to be on the short list for an RNAi Nobel.

Both Maraganore and Howard Robin, the CEO of Sirna, acknowledge that many people remain skeptical about how well RNAi will work in humans -- especially after the disappointing results with antisense and ribozymes. But they also both contend that RNA interference is far more potent than either antisense or ribozymes, and they point out that it is based on a process that occurs naturally in the body, as a way of destroying viruses.

"This process evolved to rid people of double-stranded RNA viruses, like a flu virus," says Robin. "We want to harness the same mechanism. Ribozymes and antisense don't exist in your body, so when you work with them, you have to put an awful lot into the body.

"The nice thing about siRNAs is that when a cell sees a siRNA, it knows exactly what to do with it."

Alnylam and Sirna are both designing siRNAs -- small interfering RNA molecules -- that will collaborate with proteins in the cell, forming a complex called RISC (RNA-induced silencing complex), which is the hit man that kills, or cleaves, the messenger RNA. (This whole process of RNA interference is a way of "silencing" a specific gene -- a term that has a nice Mafioso tinge to it -- for example, genes that directs cancer cells to proliferate or that crank up the production of a proteins that causes rheumatoid arthritis.)

One of the barriers that still remains for all of the RNAi companies is designing a siRNA molecule -- the essence of any RNAi-based drug -- that can find its way into the cells it's looking for (liver cells in the case of hepatitis C) and that won't degrade rapidly in the body before it can do its work. RNA interference is "easy to do in a petri dish, but harder to do in a person," says Tepper at Araios. "The challenges are finding a way to stabilize these [siRNA] molecules so they hang around for a long time, and getting them into cells in an efficient manner."

Next year will be an action-packed one for the companies seeking to commercialize the science of RNA interference.

It's likely that either Sirna or Alnylam will announce its intention to put the first RNAi-based drug into clinical trials. Both companies happen to be working on a drug to slow the progress of an eye disease called age-related macular degeneration, a very common cause of vision loss. One reason, explains Maraganore at Alnylam, is that the disease "represents a low-hanging fruit opportunity."

The siRNA molecules can be injected directly into the eye -- youch! As a result, the two key barriers to RNA interference become less important, since the molecules are already at the job site, and there's no chance for them to degrade in the bloodstream.

The odds are good that Sirna Therapeutics will announce that Craig Mello of UMass has joined its scientific advisory board, a nice boost to Sirna's prestige. The company will also probably announce a partnership with a major pharmaceutical company to develop RNAi-based drugs -- the sort of deal Alnylam sealed with Merck this year.

US and European patent examiners could rule on several patents that are crucial to any company that hopes to make RNAi-based drugs. Those decisions may lead to patent fights between Sirna and Alnylam. At Araios, Tepper says he's in the final stages of negotiating a license to "more intellectual property in the area of delivery and stability and targeting of RNAi therapeutics." Araios raised $8.7 million this fall, and plans to raise more in 2004.

It'll take a few more years, though, to prove that an RNAi-based drug can work in humans -- and to quiet the skeptics who remember all of the optimism that once surrounded antisense and ribozymes.

"I welcome the skepticism," says Maraganore. "It's our job to prove that this technology can be applied in a therapeutic context. We have a lot to do to transform this exciting science into a real product pipeline."

Scott Kirsner is a contributing editor at Fast Company. He can be reached at skirsner@verizon.net.