The National Institutes of Health last month awarded Northwestern University researcher Erik Sontheimer a two-year grant to help him develop siRNAs targeting genes involved in the inhibition of RNA interference.
According to the grant's abstract, such siRNAs could be used to boost the efficacy of a potential RNAi-based therapeutic.
Sontheimer was not available to comment on the NIH-funded research by press time. However, the abstract listed the Evanston, Ill.-based firm Silentech, which was incorporated in January, as the institution associated with the grant, suggesting the creation of yet another RNAi drugs startup.
According to the grant's abstract, although RNAi holds great potential, "one significant drawback [to the technology] is that its effect on gene expression is rarely 100 percent potent. This limitation, observed widely, is problematic when a complete cessation of gene expression is desired or required."
To overcome this limitation, Sontheimer is developing "targeted strategies to enhance the efficacy of gene silencing during commercial RNAi applications," the abstract states. These strategies include the creation of "small-molecule mimetics and RNA-based compounds that target core pathways important in determining RNAi efficacy," the abstract states, adding that such compounds could be used to enhance the efficacy of other RNAi-based drugs.
"It is our hypothesis that these genes also restrict RNAi activity in" vertebrates, including humans.
In the grant abstract, Sontheimer stated that he and his colleagues have identified a Drosophila mutant that "exhibits enhanced RNAi activity — three times stronger than normal — without any detectable side-effects."
The mutant lacks an undisclosed inhibitory gene that naturally limits RNAi efficacy by attenuating one step in the assembly of RISC, according to the abstract. "The existence of such a gene argues that natural physiological mechanisms restrict RNAi efficacy. Moreover, highly conserved homologous genes exist in all sequenced vertebrate genomes, including humans," it notes. "It is our hypothesis that these genes also restrict RNAi activity in these species."
With the NIH funding, Sontheimer and Silentech aim to "test the feasibility of developing siRNAs that block the inhibitor and thereby boost performance of an administered RNAi drug or treatment," the abstract states.
They propose to "evaluate the RNAi activity in mouse cell lines mutant for the inhibitor … [then] evaluate the RNAi activity of human and mouse cell lines treated with siRNA or shRNA [targeting] the inhibitor."
After this, the project's goal is to "evaluate the effect of inhibitor depletion by siRNA on boosting RNA-based therapies [designed to kill] prostate tumor cells and [block] influenza virus replication," the abstract states.
The NIH grant is being overseen by the National Institute of General Medical Sciences, and is worth roughly $100,000 in its first year.
Greenbacks for Greenhorns
Though details about Silentech were not immediately available, the establishment of a biotech startup by an academic is commonplace, and the RNAi field has seen its fair share of such businesses.
Alnylam Pharmaceuticals was co-founded a group of researchers who had conducted some of the field's most pioneering work, including Rockefeller University's Thomas Tuschl; the Massachusetts Institute of Technology's David Bartel; and the University of Massachusetts Medical School's Phillip Zamore.
Not all RNAi startups, however, have had the success of Alnylam. Avocel, for instance, was co-founded by Stanford University's Mark Kay and acquired by Benitec in mid-2004 (see RNAi News, 5/21/2004). Serious questions about Benitec's future have been raised, however, after the company shut down its US operations and halted its hepatitis C drug-development program, which was originally Avocel's (see RNAi News, 6/29/2006).
One-time RNAi drug firm Galenea also found the sector a difficult one. After facing competition from Alnylam in the influenza field (see RNAi News, 6/3/2005), the company sold off its flu program — its one and only RNAi project — to Nastech Pharmaceuticals (2/23/2006).