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Miragen Aims for IND in '15 as Part of Broad Corporate Strategy


NEW YORK (GenomeWeb) – As it continued work on three microRNA drug programs with partner Servier, Miragen Therapeutics is also advancing a pipeline of proprietary candidates and aims to move one into clinical testing as early as next year.

According to Miragen President and CEO William Marshall, this goal represents one part of a broad corporate strategy, dubbed 10-3-1, that envisions key milestones for the company by the end of 2017.

Under that initiative, Miragen plans to have 10 preclinically validated programs in its drug-development stable, with each having shown efficacy in an "industry-standard" disease model, successfully clearing toxicology studies, and being ready to advance into human trials, he told Gene Silencing News.

The company also has its sights set on having at least three products in clinical testing, which could include any of the Servier-partnered compounds or ones from the firm's in-house drug programs.

The final component of the 10-3-1 plan, Marshall said, is a "transforming financing event" that will support the company's in-house drug-development efforts as work with Servier and other potential collaborators continues.

While Miragen has been able to raise significant funding from private investors, including a $20 million Series B round in early 2012, he said that the company is also seriously considering an initial public offering.

Given the importance of demonstrating the potential of its technology to a successful public offering, Miragen's primary focus at the moment remains getting its drugs into the clinic, Marshall noted. And while the company is not publicly disclosing timelines for its Servier programs — which center on silencing miR-208 for chronic heart failure; inhibiting miR-15/195 for treating post-myocardial infarction remodeling; and a third, unnamed miRNA — Marshall said that it intends to file an investigational new drug application for one of its proprietary candidates in the first half of 2015.

Miragen currently has a variety of in-house programs under preclinical development, but two, focusing on miR-29 and miR-155, are the most advanced.

The miR-29 family is known to regulate extracellular matrix proteins, and all of its three members have been shown to be downregulated in different types of tissue fibrosis. Given its strong interest in cardiovascular diseases, Miragen had been studying miR-29's role in post-MI cardiac remodeling, and in 2008 company scientists reported the therapeutic benefit of introducing a miR-29 mimic in the heart.

And just this month, Miragen and collaborators at Yale University reported on the ability of synthetic miR-29 molecules to reverse and prevent fibrosis in the lung.

As described in EMBO Molecular Medicine, the researchers systemically administered miR-29b mimics into a mouse model of pulmonary fibrosis. They found that treatment restored endogenous miR-29 function, decreasing collagen expression, and blocking and reversing pulmonary fibrosis.

Though encouraged by the data, Marshall said that Miragen expects to first tackle fibrotic skin conditions, such as hypertrophic scarring, with its miR-29 mimic as local delivery poses fewer technical challenges than systemic delivery.

Once the company has demonstrated proof of concept with miR-29 replacement in this context, he said, it will go after major organ fibrosis where systemic administration is appropriate.

As for miR-155, Miragen sees potential for its inhibition in two seemingly unrelated areas: hematological cancers and amyotrophic lateral sclerosis (ALS).

When it comes to cancer, there is a subset of leukemias and lymphomas where the miRNA is "massively upregulated," Marshall said. "We've been able to demonstrate that when you inhibit 155, you induce changes in the players that are basically keeping the cells immune to programmed cell death." By preventing miR-155 expression, apoptosis can be induced in cancer cells.

In ALS, meanwhile, miR-155 appears to be involved in the destruction of motor neurons through its interaction with the immune system.

Recent work by Miragen collaborators at Brigham and Women's Hospital has demonstrated significant upregulation of the miRNA in the donated spinal cords of ALS sufferers, both with the rare hereditary form of the disease, called familial ALS, and more common sporadic ALS. The investigators also observed higher levels of miR-155 in certain activated monocytes of these patients.

"The concept is that there is some triggering event … in the spinal cord that activates and polarizes resident microglia," Marshall said. "They upregulate miR-155 and they begin to recruit activated monocytes from the periphery into the spinal cord where they contribute to the destruction of the spinal cord."

Further, the Brigham and Women's researchers found that mouse models of familial ALS in which miR-155 has been knocked out show improvements in motor functioning and survival. Additional studies by these and other investigators demonstrated similar improvements in such animals following delivery of miR-155 inhibitors to either the spinal cord or peripheral nervous system.

As such, "we think that [miR-155] could be a really interesting target for a broad spectrum of the ALS disease population," Marshall said.