Boston Biomedical last week announced it has established of a new company, AiRNA Pharmaceuticals, which has joined the ranks of those looking to develop RNAi molecules different from standard siRNAs for therapeutic applications.
AiRNA’s core technology is based on so-called asymmetric interfering RNAs, which are essentially 15-nucleotide long, asymmetric RNA duplexes with 3’ and 5’ antisense overhangs.
In a paper published in Nature Biotechnology last month, AiRNA founder and Boston Biomedical CEO Chiang Li and colleagues showed that the aiRNAs could be used to silence a target gene through the RNAi pathway in mammalian cells.
According to Li, the aiRNA technology was developed at Boston Biomedical largely in an effort to find the freedom to operate within the RNAi drugs space without the need for third-party intellectual property.
While the majority of the RNAi field’s key IP is controlled by a small handful of players, namely Alnylam Pharmaceuticals and Merck’s Sirna Therapeutics, these patent estates primarily relate to the traditional 19- to 21-nucleotide-long siRNAs.
At the same time, two companies, Dicerna Pharmaceuticals (see RNAi News, 6/12/2008) and MDRNA, are developing proprietary molecules called Dicer-substrates that are slightly longer than standard siRNAs.
Looking to carve out a niche in the space, Boston Biomedical researchers began exploring the other end of the spectrum: RNA duplexes shorter than 19 base pairs, Li told RNAi News this week.
He said that the company’s initial goal was to simply shorten a traditional siRNA, either blunt-ended or with overhangs, but found that this approach did not result in gene silencing. Then, Li said he and his colleagues began to consider the possibility that an asymmetrical molecule might prove effective.
“Fundamentally, the RISC works asymmetrically … which means it can only take on one strand [of an RNAi duplex], not both,” he said. “Yet, the siRNA is symmetrical. I thought that such a paradox may be responsible for some of the limitations encountered by siRNAs.”
After Li and his colleagues designed and tested the asymmetrical configuration, they found that the aiRNAs performed better than a standard siRNA.
“Fundamentally, the RISC works asymmetrically … which means it can only take on one strand [of an RNAi duplex], not both. Yet, the siRNA is symmetrical. I thought that such a paradox may be responsible for some of the limitations encountered by siRNAs.”
Indeed, in the Nature Biotechnology publication, Li’s research team reported that aiRNAs are capable of recruiting RISC and triggering “effective and durable silencing of a variety of genes in mammalian cells.” In one case, aiRNAs were able to suppress expression of beta-catenin in HeLa cells by 80 percent after 24 hours and by nearly 100 percent after 48 hours.
“We also determined that aiRNA mediates sequence-specific cleavage of the target mRNA between base 10 and 11 relative to the 5’ end of the antisense strand” while reducing off-target silencing by the sense strand, the authors wrote.
Specifically, after analyzing gene-array data from HeLa cells that had been transfected for 24 hours with either aiRNAs or siRNAs targeting the same sequence of beta-catenin, the investigators found that the total number of genes down-regulated by aiRNA “appeared to be smaller than the number down-regulated by the corresponding siRNA,” according to the paper.
“We next examined whether the down-regulated transcripts share partial complementarity to the siRNA or aiRNA sense strand,” they wrote. “More transcripts down-regulated by siRNA shared seven or more contiguous complementary nucleotides than those down-regulated by aiRNA, suggesting that the aiRNA sense strand causes less off-target silencing compared with the siRNA sense strand.”
To Li, the novelty of aiRNAs will be a key selling point as AiRNA pursues its near-term goal of forging one or two key licensing deals or collaborations.
“In the RNAi world, the key is intellectual property … [and] what differentiates AiRNA from other players in the game is our … IP position,” he said, adding that the aiRNA technology represents “a new, clean zone” of the RNAi patent landscape. Li noted AiRNA has filed US patent applications for its technology, though they have not yet been published by the USPTO.
Already, AiRNA is in “confidential discussions” with undisclosed companies interested in using the technology for drug development, Li said. While he declined to elaborate on the nature of those talks, he did say that AiRNA is open to a variety of different deals as long as they provide sufficient funding to the new company, in part because venture financing has become more difficult to obtain due to unfavorable market conditions.
He also stressed that while AiRNA hopes to snag a big pharma or biotech partner, the company is intent on giving alliance priority to another company Li co-founded, Cequent Pharmaceuticals, which is developing a bacteria-based delivery system for RNAi therapeutics.
Cequent President and CEO Peter Parker told RNAi News in an e-mail this week that his company currently has no plans to incorporate aiRNAs into its technology-development activities.
“If our bacterial particles show some merit, we could think about loading them with these asymmetric constructs,” he wrote, “but that is far from our current set of goals.”
At the same time, AiRNA is weighing its options when it comes to using aiRNAs for research purposes, Li said.
“I have already received a lot of inquiries from biomedical researchers asking where they can order aiRNA reagents,” he said. And while Li had considered the possibility of forming a separate company to develop aiRNAs as research tools, he said that at this point, “we’d prefer to collaborate with an established reagent company” that can oversee product development and commercialization.
Despite its strong interest in partnerships, AiRNA will also have its own drug pipeline, Li noted. Already, the company is conducting lead optimization work for an oncology program that could yield an investigational new drug application filing by as early as late 2009.
He added that the company is also considering programs in viral and inflammatory diseases.