miRagen Therapeutics CEO William S. Marshall notes, “A lot of pharmaceutical companies have announced they are getting out of the cardiovascular research arena.” While watching experienced drug developers head for the exits might serve as a red flag to some, Marshall prefers to concentrate on the opportunity. Heart disease remains the number one cause of death worldwide, and the CEO contends that “although most of the existing treatments are largely palliative, nobody seems to expect much further development with traditional approaches.” These conditions open the window of opportunity for radically different approaches to treatment – and Miragen Therapeutics is pursuing just such an approach in the development of microRNA (miRNA) technology.
miRNAs, which were discovered only 15 years ago, are short sequences of nucleotides that occur naturally within cells. It is estimated that there are about 1100 microRNA coding regions in the human genome, but only 80 to 150 specific miRNAs are expressed within a cell type. These miRNAs play an important role in regulating gene function and the expression of entire pathways by binding to an untranslated sequence near the gene. The greater the quantity of a specific miRNA present, the less the corresponding gene will be expressed. By controlling the amount of miRNA that binds, it is thus possible to up or down regulate genes. This control can be accomplished by creating miRNA mimics to down regulate a gene (mimics can bind to the same sequence as the original miRNA) or inhibitors to increase gene expression (inhibitors bind to the miRNA and thus prevent it from binding to the gene).
While miRNA activity in general may be scientifically interesting, what makes it important as a potential therapeutic are the differing levels of specific miRNAs within diseased cells when compared to normal cells. Marshall explains: “Think of a stereo equalizer with a thousand dials. If a particular dial is set to high or too low, it throws everything out of whack. The same is true for the levels of different miRNA within a cell.” Identifying the specific miRNAs that are over or underrepresented in disease states presents an opportunity to correct these problems by changing miRNA activity level.
miRagen is focused on several specific disease drivers that contribute to a variety of cardiovascular conditions including chronic heart failure.The Company believes that many of these are at least in part caused by changes in miRNA levels. In diseased cardiomyocytes, for example, increased expression of a specific miRNA suppresses the creation of many pro-survival factors that in turn lead to cell death. Inhibiting that specific microRNA could prevent the death of the cardiomyocytes, which then could prevent the induction of heart failure. Another specific miRNA is down regulated in heart disease and allows for the over-expression of pro-fibrotic genes leading to fibrosis, which inhibits normal heart function. Adding more of that specific microRNA to the cell could prevent that sequence of events and potentially avert the development of fibrosis. Through its research efforts to date, miRagen has identified and validated several specific pathways and the associated miRNA targets and currently is working to optimize lead molecules to mimic or inhibit each miRNA.
A core challenge to miRNA therapeutics is delivery: it is difficult to get sufficient levels of the nucleotide sequences into specific tissues and cells. But in the clinical conditions the Company initially is pursuing, including chronic heart failure, the challenge becomes less daunting because local delivery is possible when a catheter is routinely inserted as part of treatment. This local delivery additionally allows for substantially reduced doses of the therapeutic agent. miRagen also is pursuing new opportunities for systemic delivery of its drugs including a collaboration with Cambridge, Massachusetts, based Archemix Corp, which was announced at the end of July. Archemix focuses on aptamers, which are composed of nucleic acids akin to miRNAs. This common chemistry makes it feasible to attach the two together. Aptamers with miRNA modulators attached can be designed to bind to specific proteins that are readily internalized by particular cell types. The internalization of the miRNA-aptamer complex could allow for the achievement of therapeutic levels of miRNA drugs within target cells to a more substantial degree than treatment with miRNA modulators alone.
miRagen was founded in August of 2007 and brought in an initial round of $8M in Series A funding in the spring of 2008. The company hit the milestones necessary to bring in the second tranche of this round in December of 2008 and also secured an additional $4M Series A extension inMay 2008. Marshall says the Company’s current financing puts it “in good shape through 2010.”
With investors being increasingly risk averse, it is challenging to raise funding for a new drug let a alone an entirely new modality. To miRagen’s success in garnering funding to date, Marshall comments on the dual benefits inherent to its focus in the cardiovascular market. By picking a particular therapeutic area, Marshall believes the company increases it chances at success: “If you don’t have an intense focus, you’ll never do anything very well.” But in choosing the cardiovascular market, miRagen has not limited the market opportunity that could drive returns to investors: “We’re talking about the number one cause of death that also has huge morbidity costs.”
miRagen will be among the companies presenting at the Rocky Mountain Life Science Investor Conference on Thursday, September 17 in Denver.
