Skip to main content
Premium Trial:

Request an Annual Quote

Miragen Adds Myeloproliferative Disease Drug to Pipeline, Sees IND in 2012


By Doug Macron

BOSTON — Miragen Therapeutics has expanded its drug pipeline, adding the myeloproliferative disease polycythemia vera to the list of conditions it aims to address through microRNA inhibition, the company's top executive said this week.

Speaking at the Tides Oligonucleotide and Peptide Research, Technology, and Product Development conference here, Miragen President and CEO Bill Marshall said that that work in polycythemia vera is promising, and that the program could potentially reach the clinic ahead of a longer-standing program in chronic heart failure.

An investigational new drug application filing for at least one of the drugs is expected by the end of 2012.

Myeloproliferative disorders are characterized by the overproduction of cells by bone marrow. In polycythemia vera, patients produce too many red blood cells, which are forced out of the bone marrow into other organs and tissues, including the spleen.

According to Marshall, the polycythemia vera indication was “an opportunistic one” that grew out of a screen to identify miRNAs associated with myocardial infarction. Miragen researchers identified miR-451 through the screen, and in subsequent experiments found that it is “highly enriched in myeloid cells,” leading the company to focus on it for myeloproliferative diseases, he said at Tides.

Currently, there are no “disease-modifying therapies” available for polycythemia vera patients, who typically present with abdomen tenderness related to their enlarged spleens, he explained. Because patients commonly die from thrombosis, the typical course of treatment involves administration of hydroxyurea.

However, patients often become resistant to the drug and thereafter are bled to address the hyperproliferation of red blood cells, Marshall said.

Recent research from the lab of Miragen co-founder and University of Texas Southwestern researcher Eric Olson suggests that miR-451 plays a key role in erythropoiesis. According to Marshall, additional work conducted by Miragen researchers shows that inhibiting the miRNA can return hematocrit levels to normal in mouse models of polycythemia vera.

“What we're doing is inactivating the ability of the cells to proliferate,” he said, adding that continued treatment with the miR-451 antagonist, dubbed MGN-4893, does not appear to affect mice adversely even once their hematocrit levels have been restored to baseline.

Miragen received orphan drug status from the US Food and Drug Administration for MGN-4893 earlier this year.

Meantime, the company continues to advance its lead program in chronic heart failure, which is targeting miR-208, Marshall said.

“When you stress the heart, you develop something called pathological hypertrophy, an enlargement of the heart, and persistent stress eventually leads to cardiomyopathy and eventual heart failure,” he said this week.

Driving the company's focus on this program is work published by Olson in 2008 linking the heart-specific miRNA, which is encoded by an intron of the alpha-MHC gene, to cardiomyocyte hypertrophy, fibrosis, and the expression of beta-MHC in response to stress and hypothyroidism.

As Olson noted in an earlier publication, a key characteristic of cardiac hypertrophy, which frequently leads to heart failure, is “the re-activation of a set of fetal cardiac genes, including those encoding … fetal isoforms of contractile proteins such as beta-myosin heavy chain.”

“The consequences of fetal gene expression on cardiac function and remodeling are not completely understood, but the up-regulation of beta-MHC, a slow ATPase, and down-regulation of alpha-MHC, a fast-contracting ATPase, in response to stress has been implicated in the diminution of cardiac function,” Olson wrote.

Marshall noted this week that it appears that miR-208 is “a key linchpin” between pathologic hypertrophy and physiologic hypertrophy, which occurs as a normal consequence of exercise, is reversible, and is not associated with fibrosis.

[ pagebreak ]

Notably, Miragen researchers have found that miR-208 is closely associated with another miRNA, miR-499, and that suppression of both is required to see a therapeutic benefit, he said.

When a miR-208 antagonist is administered in animals, its target is inhibited within hours or days, he said. “What is interesting is that it takes a week to two weeks before we begin to see [down-regulation of] … miR-499,” which is believed to reside in a non-translated myocin gene.

“We've been able to find that miR-208 targets a factor important in the expression of [miR-499], and the kinetics are such that once we get 208 down, 499 begins to come down, beta-myosin heavy chain then begins to come down, and then we see the effects are cardiac remodeling,” he said.

“This was a key observation … because early on we were looking for effects too early in the pharmacology,” Marshall added. “Now that we know the time course of this, we are monitoring it at the appropriate times. This is also going to be key in terms of guiding our clinical evaluations.”

Additionally, because miR-499 can be found in circulation, it is “a very nice biomarker,” he said.

Miragen's chronic heart failure drug, called MGN-9103, is currently being evaluated in a second-species efficacy study, which “tend to take a fair amount of time," Marshall told Gene Silencing News. As such, MGN-4893 may be ready for the clinic first.

Either way, Miragen expects to have at least one drug ready for an IND filing “within a year to a year and a half.”

Have topics you'd like to see covered in Gene Silencing News? Contact the editor
at dmacron [at] genomeweb [.] com

The Scan

Study Points to Tuberculosis Protection by Gaucher Disease Mutation

A mutation linked to Gaucher disease in the Ashkenazi Jewish population appears to boost Mycobacterium tuberculosis resistance in a zebrafish model of the lysosomal storage condition, a new PNAS study finds.

SpliceVault Portal Provides Look at RNA Splicing Changes Linked to Genetic Variants

The portal, described in Nature Genetics, houses variant-related messenger RNA splicing insights drawn from RNA sequencing data in nearly 335,700 samples — a set known as the 300K-RNA resource.

Automated Sequencing Pipeline Appears to Allow Rapid SARS-CoV-2 Lineage Detection in Nevada Study

Researchers in the Journal of Molecular Diagnostics describe and assess a Clear Labs Dx automated workflow, sequencing, and bioinformatic analysis method for quickly identifying SARS-CoV-2 lineages.

UK Team Presents Genetic, Epigenetic Sequencing Method

Using enzymatic DNA preparation steps, researchers in Nature Biotechnology develop a strategy for sequencing DNA, along with 5-methylcytosine and 5-hydroxymethylcytosine, on existing sequencers.