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Mirna Presents Animal Data on miRNA Mimics in Liver Cancer, Aims for Phase I in 2013

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By Doug Macron

Mirna Therapeutics this week released new details on its efforts to develop a microRNA-based treatment for liver cancer, reporting data showing that five mimics of miRNAs with tumor-suppressor activity could “significantly” inhibit tumor growth in a mouse model of the disease.

Based on these and other findings, Mirna is advancing its lead miRNA drug candidate for solid tumors and expects to begin phase I testing in early 2013, President and CEO Paul Lammers told Gene Silencing News.

Mirna presented the data at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics and the 2011 CPRIT Innovations in Cancer Prevention and Research conference.

According to the company, its researchers transfected liver cancer cells with the miRNA mimics and analyzed them four to eight days later for proliferation.

Cells were also transfected with an siRNA targeting kinesin family member 11, which lowers proliferation by 60 to 80 percent in hepatocellular carcinoma cell lines, in order to provide a comparison point for the anti-proliferative activity of the miRNAs.

Eight miRNAs demonstrated the highest “capacity to significantly inhibit the proliferation of multiple HCC cell lines,” the company said in a poster from the AACR-NCI-EORTC event. These included miR-34, which is the basis for Mirna's lead drug candidate; miR-16; and let-7. The other miRNAs remain undisclosed.

The investigators then evaluated four undisclosed siRNA-delivery technologies in an orthotopic mouse model of human liver cancer using either a mimic of miR-34 or negative control.

Analysis by qRT-PCR revealed that the least effective delivery approach boosted levels of miR-34 in the mouse livers by around 40 copies per cell. The most effective — a lipid-based nanoparticle system — increased levels by more than 100,000 copies per cell and also delivered 10,000 copies of the miR-34 mimic per cell to spleen, lung, kidney, and pancreas one day after injection, Mirna said.

Lammers noted that Mirna expects to use this delivery system with its first drug candidate.

To assess the therapeutic effect of the miRNAs, mimics of miR-34, let-7, and two other undisclosed miRNAs were encapsulated in the nanoparticles of the best-performing delivery system and then frozen. Model mice were then given either one of the miRNA mimics, a negative control, or no treatment daily for three days and then every other day for 10 days.

“Four mice per treatment group were sacrificed on the thirteenth day after the initiation of treatment, while three animals per group were selected for five additional injections of formulated miRNA,” the company said. The mice were monitored for behavior and serum alpha fetoprotein levels, which were used to judge tumor growth.

Once AFP levels in the mice reached excessive levels or they stopped grooming themselves, the animals were sacrificed.

For the control mice, AFP levels increased exponentially during the two weeks following the start of the study. Levels in animals receiving the let-7 mimic were “significantly lower than the control groups,” but still higher than in mice receiving other miRNA mimics.

AFP levels in mice treated with miR-34 and two other unnamed miRNAs were unchanged during the treatment period, and most of them “actually had lower serum AFP levels after the treatment period than they had prior to the initiation of treatment,” Mirna noted.

“In effect, [this] meant there was a regression of the liver cancer,” an effect confirmed after the animals were sacrificed and analyzed, Lammers said.

Specifically, the team found no tumors in mice receiving one of the undisclosed miRNA mimics, and an immunohistochemical assay revealed that the “majority” of mice in the treatment groups contained no tumor cells at all.

Additional animals from the treatment groups received additional dosing for nine days. All four miRNAs “significantly increased the survival rates” of these animals, while those receiving mimics of two undisclosed miRNAs failed to develop tumors large enough to meet the moribund criteria set by the company during the study.

Despite the positive effects observed with the two undisclosed miRNAs, Mirna still intends to take its miR-34 mimic into the clinic first, Lammer said.

“We have done a lot of work on miR-34, and it is one of the most widely published microRNAs, as well,” he said. There is clearly a lot of interest” in it.

Notably, miR-34 has been linked to the tumor-suppressor protein p53. In 2007, for instance, two research groups separately reported that p53 directly targets members of the miR-34 family, suggesting the miRNA is a key component of the p53 network (GSN 6/7/2007).

At the same time, Mirna has built an intellectual property estate around the therapeutic use of miR-34. Earlier this year, the company announced that the US Patent and Trademark Office had allowed claims within an application describing methods of reducing cancer cell viability by introducing the miRNA into tumor cells (GSN 4/7/2011).

“Perhaps there is a luxury of riches we have because we have three phenomenal microRNAs that could all be very effective in liver cancer,” Lammers said. However, “we have to make choices in life,” especially as a small biotech with limited resources.

As part of its efforts to advance its miR-34 candidate, Mirna is in licensing talks with the owner of the drug-delivery technology it hopes to use with the drug, he said, although he declined to provide additional details.

The company has also identified oligo manufacturers and is preparing to conduct investigational new drug application-enabling toxicology work. Should everything remain on schedule, Mirna plans to file the IND by the end of 2012 and begin human testing early the next year.


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