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Mirna Releases Preclinical Data on miRNA-Replacement Rx, Aims for Clinic in 2011


Asuragen subsidiary Mirna Therapeutics this week unveiled preclinical data showing that one of its microRNA mimics inhibited tumor growth and metastases in a variety of animal models without toxicity.

These data, along with the publication last week of a report showing that therapeutic miRNA delivery could suppress tumorigenesis in a mouse model of liver cancer, suggest that miRNA replacement could be a safe and effective therapeutic strategy for cancer, Mirna CEO Matt Winkler told RNAi News this week.

As such, Mirna expects to begin clinical testing of its first drug candidate by 2011, he said.

Mirna's drug, dubbed miR-Rx34, is designed to mimic miR-34, which has been shown to be down-regulated in multiple human cancers and associated with the p53 tumor-suppressor network.

According to Mirna, systemic administration of the agent to mouse models using a recently in-licensed neutral lipid-based delivery vehicle inhibited the proliferation and viability of a "variety of cultured cancer cells, including those derived from patients with melanoma, lung, prostate, liver, and colon cancers."

Additionally, miR-Rx34 inhibited the growth and metastasis of established human tumors in mouse models of lung and prostate cancer, the company's two primary indications of interest. Mirna researchers also compared the effects of the lipid delivery vehicle, either alone or with the miRNA payload, and found no signs of toxicity or immunogenicity.

Winkler attributed miR-Rx34's apparent safety to a combination of the drug's potency and the fact that miRNAs are a natural part of human biology. Importantly, Mirna is also focusing on miRNAs that are already present at high levels in normal cells, but suppressed in tumors.

While the drug is not targeted to cancer cells, the doses required to achieve a therapeutic effect are so low that normal cells appear to be unaffected, he said. "But when you add a small amount to tumor cells, it triggers cell death [and] tumor regression, [and] inhibits metastases."

At the same time, "microRNAs have a billion years of evolution fine-tuning their sequence," Winkler noted. As a "natural part of normal cells," agents that mimic the small RNAs are unlikely to have any adverse effects.

In addition to miR-Rx34, Mirna has another mature miRNA mimic at roughly the same stage of development. Winkler said that, like miR-Rx34, the other drug is "minimally modified" to enhance uptake and stability, but he declined to provide additional details.

Although Mirna announced its plan to reach the clinic by 2011 in conjunction with the release of data on miR-Rx34, Winkler noted that a decision has not been made on which of the company's drugs will enter human testing first. Selection of a lead candidate, he added, will be driven by data from work leading up to an investigational new drug application.

Mirna has publicly disclosed three oncology indications — non-small cell lung cancer, metastatic prostate cancer, and acute myeloid leukemia — as its areas of interest. In addition, the company has investigated the possibility of using miRNA-replacement therapy to sensitize cancer cells to conventional chemotherapeutics (see RNAi News, 6/19/2008).

But it has now limited itself to developing miRNA mimics as stand-alone drugs for lung and prostate cancer, Winkler said.

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The development of miRNA drugs, he said, is "constrained … by the nature of the drug-development process in the United States. I would love to be expanding out and looking at how [the agents] synergize with chemotherapy, but we need to look at how they function as standalone entities first."

As for the decision to put leukemia on the backburner, he noted that Mirna doesn't currently have the resources to pursue the indication.


Taking a slightly different approach to miRNA-replacement therapy than Mirna, a team of investigators led by Johns Hopkins University School of Medicine researcher Joshua Mendell last week published in Cell data showing that an miRNA mimic delivered using a viral vector, rather than a lipid carrier, could combat cancer in animal models.

"As a consequence of the important functions provided by miRNAs in cancer cells, potential therapeutic approaches that target this pathway have recently attracted attention," they wrote. "Although significant focus in this area has been directed toward antisense-mediated inhibition of oncogenic miRNAs, several lines of evidence suggest that miRNA replacement represents an equally viable, if not more efficacious, strategy."

To test this hypothesis, the researchers focused on hepatocellular carcinoma, since the liver is easily targeted by both viral and non-viral drug-delivery systems, and miR-26a, which is expressed at high levels in the normal adult liver but at low levels in liver tumors and therefore expected to be well-tolerated by normal cells.

In vitro, expression of miR-26a in liver cancer cells induced "cell-cycle arrest associated with direct targeting of cyclins D2 and E2," they wrote in Cell.

Meanwhile, in a mouse model of liver cancer, systemic administration of the miRNA using an adeno-associated virus inhibited cancer cell proliferation, induced tumor-specific apoptosis, and significant protection for disease progression without apparent toxicity.

These findings "demonstrate that therapeutic delivery of an miRNA can result in tumor suppression even in a setting where the initiating oncogene is not targeted," the investigators stated. "This establishes the principle that miRNAs may be useful as anticancer agents through their ability to broadly regulate cancer cell proliferation and survival."

In addition, the study involved the treatment of existing tumors with an miRNA, "a paradigm closely related to the clinical scenarios in which such therapies would be employed," while leaving normal tissue unaffected, they added.

"Although the molecular basis of this specificity requires further investigation, it is likely that the high physiologic expression of miR-26a in normal hepatocytes confers tolerance to exogenous administration of this miRNA," Mendell and colleagues wrote. "In contrast, the specific reduction of miR-26a in neoplastic cells and their sensitivity to its restored expression underscores the contribution of loss-of-function of this miRNA to tumorigenesis in this setting."

Although the delivery of miR-26a "confers dramatic tumor protection," the research team noted that there are likely to be miRNAs with equal or greater therapeutic potential that have yet to be functionally characterized.

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Underscoring Mirna's approach to using miRNAs therapeutically, they added that the most promising of such miRNAs will likely be "highly expressed in a wide variety of normal tissues, be under-expressed in the disease state being studied, and, when evaluated using in vitro or in vivo models, demonstrate specific phenotypic effects in disease cells while sparing normal cells.

"While there clearly remains significant work to be done both in identifying such miRNAs and optimizing their controlled delivery, our findings highlight the therapeutic promise of this approach," they concluded.

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