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Alnylam Sees Opportunity in Turning Genes On, And Off

Xconomy Boston — 

A lot has been written about how Alnylam Pharmaceuticals, and plenty of other companies, see a gold mine in turning off problem genes through drugs based on the biological phenomenon called RNA interference, or RNAi. It turns out that Alnylam (NASDAQ: ALNY), the highflying Cambridge, MA-based biotech company built around RNAi, sees another big opportunity in doing the exact opposite—turning on certain genes that can help combat disease.

The new field is called RNA activation, or RNAa for short. Just like it did when it corralled intellectual property for its bread-and-butter RNAi business, Alnylam took the strategy of looking at the state-of-the-art and grabbing technology licenses that would give it a dominant position in the emerging field, says CEO John Maraganore. Last month, Alnylam said it obtained what it considers the field’s seminal IP from the Salk Institute, the University of Texas Southwestern Medical Center in Dallas, and the University of California, San Francisco.

The fundamental idea here is that sometimes people lack enough of a good protein to stay healthy. For example, researchers would like to know what would happen to people with cancer if a drug could stimulate production of the P53 protein, a well-known tumor suppressor, or P21, a protein that acts as a “stop signal” for cell division. Or, what would happen if researchers could develop a drug to activate a gene that’s otherwise faulty for patients with a single gene defect, like the one that causes cystic fibrosis, a fatal lung disease among children and young adults?

“This is the exact opposite of what we do with RNAi,” says Maraganore. “All diseases are from an overexpression or an underexpression of proteins. When you have an underexpression of certain proteins, that’s where RNAa can be applied.”

The opportunity for RNAa isn’t as broad as with the company’s original gene-silencing technology, because more diseases are caused when the body has too much of a certain physiological activity going on, Maraganore says. RNAa work is still in earliest scientific stages, yet the strategy has impressed Wall Street.

“Although the technology is at an early stage and much remains to be learned and validated about the mechanisms involved, we do believe that it shows the potential to become a powerful approach to RNA-based therapeutics,” said Michael King, an analyst with Rodman & Renshaw, in a note to clients last month about Alnylam’s venture into RNAa.

The RNAa work is being done with the same type of molecules used for RNAi—RNA strands which are 21 nucleotides, or chemical units, in length, Maraganore says. The company has obtained eight patents which it considers critical to the field, and like with RNAi, it hopes to essentially set up a toll booth for other companies who want to develop drugs using the technology. “If the science progresses as well as we hope, it will enable us to do deals,” with large drugmakers, Maraganore says.

The early work in RNAa dates back to 2004 in Fred Gage‘s lab at the Salk Institute in San Diego. He showed that double-stranded RNA molecules could prompt genes to produce proteins, Maraganore says. “People were scratching their heads at the time,” Maraganore says. “People viewed it as interesting, but probably some artifact that was not reproducible.”

Two years later, Long-Cheng Li of UCSF showed that a double-stranded RNA could stimulate significant activation of the P21 gene that produced anti-tumor activity in bladder cancer cells. Last year, David Corey of the University of Texas-Southwestern Medical Center in Dallas showed in Nature Chemical Biology that “activating RNAs can predictably manipulate physiologically relevant cellular pathways,” according to King, the Rodman & Renshaw analyst.

For now, Alnylam is looking to test some of its ideas about RNAa with academic collaborators, including Corey’s lab and Li’s lab. Regulators will need to be convinced the approach is safe before trials are allowed in humans. Maraganore didn’t provide a date, but says “it could be a few years” before the company enters human trials with an RNAa-based drug. By that time, maybe RNAa will be the hot new technology ready to push RNAi off the covers of the scientific journals.

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