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BioMolecular Therapeutics Joins Ranks of RNAi Drug Developers

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South Korea's BioMolecular Therapeutics this week announced that it has thrown its hat into the RNAi drugs ring, becoming the latest startup to try to develop therapeutics based on the gene-silencing technology.

According to the company, its core technology involves the use of asymmetric siRNAs designed to trigger an RNAi effect while avoiding the immune stimulation associated with standard 19-nucleotide-long siRNAs.

Specifically, BioMolecular's so-called asymmetric shorter-duplex siRNAs are 15 to 16 base pairs long and feature 3' overhangs on only the antisense strand, compared with the 3' overhangs on both strands of conventional siRNAs.

In a paper published last year in Molecular Therapy, company founders, along with collaborators at Beth Israel Deaconess Medical Center and Boston Biomedical, reported that asiRNAs were capable of triggering gene silencing with reduced off-target effects.

"Using … modified asiRNA backbone structures, we were able to reduce multiple nonspecific effects triggered by conventional siRNAs, such as off-target effect mediated by the sense strand and saturation of the RNAi machinery," the team wrote.

"While siRNAs were originally selected to circumvent the innate immune surveillance system, several reports have demonstrated that synthetic siRNAs can trigger nonspecific innate immune responses," they added, citing a 2008 Nature paper showing that any dsRNA at least 21 nucleotides in length activated toll-like receptor 3 (GSN 3/27/2008).

Notably, that paper was co-authored by University of Kentucky researcher Jayakrishna Ambati, who sits on BioMolecular's scientific advisory board. It also focused on two siRNA-based wet age-related macular degeneration drugs — Opko Health's bevasiranib and Sirna/Allergan's AGN211745 — that had been tested in humans but were ultimately dropped due to poor clinical data.

Given that Ambati's Nature paper also demonstrated that siRNAs with duplex regions shorter than 19 base pairs had reduced or no immune activation, "we expect that shorter-duplex siRNA may circumvent or reduce the challenge of nonspecific immune responses observed with [conventional siRNAs], which is especially critical in therapeutic development of siRNA-based drugs," the Molecular Therapy paper concludes.

In addition to allowing its RNAi agents to sidestep unwanted immune stimulation, BioMolecular said that its asiRNAs are also novel enough to fall outside of the intellectual property held by other companies in the field, including Alnylam Pharmaceuticals and its Tuschl-I and Tuschl-II patent families.

BioMolecular's core IP is a filing with the World Intellectual Property Organization, No. WO/2009/078685, entitled "Novel siRNA Structure for Minimizing Off-Target Effects and Relaxing Saturation of RNAi Machinery and the Use Thereof."

According to that application's abstract, the "invention relates to a double-stranded small interfering RNA molecule comprising a 19 [to] 21 nucleotide antisense strand and a 15 [to] 19 [nucleotide] sense strand having a sequence complementary to the antisense sequence, wherein the 5' end of the antisense strand has a blunt end and the 3' end of the antisense strand has an overhang, and to a method for silencing the expression of a target gene using the siRNA molecule."

Leveraging Ambati's experience with RNAi and AMD, BioMolecular has initially set its sights on developing an asiRNA-based treatment for AMD. However, the company is also collaborating with Boston BioMedical on cancer treatments using the technology.

Interestingly, about two years ago Boston Biomedical founded AiRNA Pharmaceuticals to advance therapeutics based on technology similar to asiRNAs called asymmetric interfering RNAs, or aiRNAs (GSN 12/11/2008). Boston Biomedical Founder Chiang Li was also a co-author of the Molecular Therapy paper.

Unlike asiRNAs, however, aiRNAs have antisense overhangs on both the 3' and 5' ends.

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