By Doug Macron
BOSTON — Marina Biotech this week provided a few new details on its efforts to develop microRNA inhibitors, showing that single-stranded oligos modified with a proprietary technology could block expression of a key miRNA in vitro at levels similar to Santaris Pharma's locked nucleic acids.
Specifically, Marina researchers tested oligos modified with the company's conformationally restricted nucleotide technology, which essentially comprises nucleotide analogs to which the C2' and C4' carbon bonds of the ribose ring are linked. CRNs are similar to LNAs, but have a longer linker and an oxygen atom in a different location.
According to Michael Templin, Marina's senior vice president of preclinical development, the company tested oligos complementary to miR-21, an miRNA implicated in a variety of cancers and fibrosis, and found that ones modified with the CRN technology had a melting temperature about three degrees higher than all-DNA oligos, an effect “pretty similar to what we get for LNAs.”
Templin cautioned, however, that such results are, “of course, sequence-dependent … modification-dependent … and assay-dependent.”
When examined in a dual-luciferase assay, the CRN-modified miR-21 antagonists were able to achieve a greater than 90 percent knockdown of their target at a 5 nM concentration, compared with about 30 percent inhibition with the all-DNA oligo, he said.
Templin, who made his comments at this year's Tides Oligonucleotide and Peptide Research, Technology, and Product Development conference in Boston, noted that the CRN technology is still in the earliest stages of development, and that Marina is currently evaluating whether it can achieve similar levels of miRNA inhibition at lower concentrations.
“All indications are that it is much more potent” and will prove efficacious at lower concentrations in ways that are “very comparable” to LNAs.
Looking beyond its core focus of RNAi has been a priority for Marina for some time.
Earlier this year, President and CEO Michael French told attendees at the BIO CEO and Investor conference that “diversity is critical to success,” and stressed that “no single [drug] modality” will be able to address all diseases (GSN 2/17/2011).
French highlighted Marina's CRN technology as a key aspect of the company's bid to offer big pharmas a range of technologies from which to choose as they consider partnership opportunities since it can be used to create single-stranded oligos that don't face the same delivery hurdles as double-stranded ones such as siRNAs.
Indeed, as Templin noted this week, administration without the need for a delivery vehicle is preferable, and Marina has data showing that CRN-modified single-stranded oligos can reach tissues including the liver, lung, and kidney in saline alone. However, he said, some applications will likely require the use of delivery vehicles.
Late last year, Marina released data from in vivo experiments showing that miRNA mimics could be delivered to tumor cells in liver, lung, and heart tissues at high levels when formulated with its di-alkylated amino acid, or DiLA2, delivery system (GSN 9/16/2010). This work was conducted in collaboration with miRNA drug developer Mirna Therapeutics.
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