WALTHAM, Mass. -- Santaris Pharma and the University of Copenhagen announced this week that they have formed a research consortium in order to identify associations between microRNAs and human disease and create novel miRNA-targeting drugs that could enter human testing as early as next year.
The effort is being supported by a two-year grant worth €1.3 million ($1.6 million) from the Danish government's Advanced Technology Foundation. Santaris and the university have committed an additional €1.3 million, bringing the initial budget for the consortium to €2.6 million.
According to Sakari Kauppinen, head of the miRNA research unit in the university's department of medical biochemistry and genetics and associate director of miRNA research at Santaris, the partners hope to identify novel associations between miRNAs and human diseases, especially cancer. The university will have the first right to patent the miRNAs as drug targets, while Santaris will have first rights to license the targets for drug development using its locked nucleic acid technology.
LNAs are a class of nucleic acid analogs in which the ribose ring is locked by a methylene bridge connecting the 2'-O atom with the 4'-O atom, features designed to increase affinity and stability. Santaris holds the exclusive global rights to LNAs for therapeutic applications, while Exiqon owns the research and diagnostic rights to molecules.
"We asked if we could use short LNA antagonists â€¦ to shift the dosing regime lower â€¦ [while] still retaining high specificity in vivo."
Santaris believes that LNAs can be used to block the action of miRNAs found to be involved with human disease. Kauppinen told RNAi News this week on the sidelines of the Gene Expression System's RNAi 2006 Boston meeting in Waltham, Mass., that the company hopes to begin preclinical testing of an miRNA-targeting LNA drug late this year or early next year. Phase I studies are expected to start as early as late 2007, he added.
Kauppinen said that although the miRNA consortium will primarily be focused on colon, breast, and lung cancers, it is also investigating blood cancers, neurological disorders, and metabolic diseases. During his presentation at the RNAi 2006 meeting, he noted that early data suggests miRNAs play a role in conditions ranging from Burkitt's lymphoma to fragile X mental retardation, spinal muscular dystrophy, and Tourette's syndrome.
Kauppinen told RNAi News that Santaris and the University of Copenhagen are actively seeking additional collaborators, both from academia and industry, for the miRNA consortium, but that discussions held thus far have been preliminary.
Improving on a Good Idea
Santaris is not the only company that thinks miRNAs will make good drug targets. Late last year, Rockefeller University researcher Markus Stoffel published data in Nature showing that a new class of oligos termed antagomirs could be used to selectively inhibit microRNAs in vivo (see RNAi News, 11/4/2005). Alnylam Pharmaceuticals holds the exclusive rights to antagomirs for all therapeutic indications.
Antagomirs are chemically modified, cholesterol-conjugated single-stranded RNA analogues. Using these compounds, Stoffel and his colleagues were able to knock down a number of miRNAs including miR-122, which is associated with cholesterol biosynthesis. By targeting this miRNA, they were able to cut plasma cholesterol levels in mice by about 40 percent.
However, as Kauppinen pointed out, the antagomir dose used by Stoffel and colleagues -- 80 mg/kg -- is very high, echoing comments from University of North Carolina researcher Scott Hammond in an article in the March issue of Trends in Molecular Medicine.
Hammond noted that while Stoffel's work "demonstrated remarkably effective inhibition of miRNAs in vivo â€¦ the required intravenous dosage is high."
"Therefore, we asked if we could use short LNA antagonists â€¦ to shift the dosing regimen lower â€¦ [while] still retaining high specificity in vivo," he said. Hammond suggested in his article that researchers still need to find "strategies â€¦ to reduce dosage to manageable levels."
According to Kauppinen, Santaris recently conducted experiments in which mice were administered intravenous doses of 16-mer LNAs targeting miR-122 in doses ranging from 2.5 mg/kg to 25 mg/kg. Not only did these so-called LNA antimirs significantly down-regulate the target miRNA, but treated mice experienced up to a 40-percent drop in plasma cholesterol levels, he said.
Kauppinen said during his presentation that miRNA knockdown was observed as far as day 23, although cholesterol levels rose as time progressed.
"Basically, we followed the regimen Stoffel and [his] colleagues used" but with significantly lower doses of miRNA antagonists, Kauppinen said.
He noted that these data have been submitted for publication and will be reported at the upcoming 71st Cold Spring Harbor Symposium being held May 31 to June 5.
-- Doug Macron ([email protected])