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Mouse Model Startup Mirimus Sets Sights on Industry Customers

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As its contract with the National Cancer Institute nears completion, startup Mirimus is hoping to begin adding drug companies to the list of customers for its inducible-RNAi mouse models, Mirimus CEO Prem Premsrirut said this week.

At this point, the majority of Mirimus' clients are academics, which have been easier to approach given Mirimus' status as a spinout of Cold Spring Harbor Laboratory, she told Gene Silencing News. “The commercial customers we're aiming for ... will take a little bit more time.”

Securing industry deals has been somewhat of a challenge in part because those in big pharma and biotech are not “fully aware of [Mirimus'] technology and how it can be put into their current drug-development process,” Premsrirut added. “The technology is still fairly new, and maybe they're looking for a little more validation than what's currently out there.”

Mirimus was founded to commercialize technologies — based on the work of CSHL researchers Greg Hannon and Scott Lowe, and Harvard Medical School's Stephen Elledge — used for the creation of genetically engineered mouse models.

The first step in this process involves sensor array technology that allows for the large-scale identification of highly effective shRNAs.

The approach, as described in a 2011 paper in Molecular Cell, involves the construction of RNAi reporters covering all possible target sites in selected mammalian transcripts. In that paper, CSHL researchers wrote that the method showed that “potent shRNAs share various predicted and previously unknown features associated with specific microRNA processing steps,” and offered a new tool for their identification.

“A lot of companies sell short hairpin RNAs or siRNAs, and they are effective in silencing the gene target only when they are used at very high concentrations,” which isn't much of an issue in vitro, Premsrirut said. “However, when you want to move into an animal model, in order for [gene knockdown] to be non-variable and potent … you need to have an RNAi trigger that works very [well] at low concentrations.

“There is no other company that uses technology like ours where you can actually identify the sequences that work at [the required] potency and concentration” for in vivo experimentation, she said.

Once optimal shRNA sequences have been identified, Mirimus then introduces them into mouse embryonic stem cells at specific genomic loci and with a single copy integration to create custom gene-silencing models, according to Premsrirut. Because the shRNAs incorporate tetracycline-regulated promoters, target knockdown can be turned on or off.

Details about the technology were published last year in Cell.

“Depending on how we design the mouse model, it can be used for global gene suppression in all the tissues within the mouse or it can actually be [done] in a tissue-specific manner where you have specific gene silencing in a desired cell type or organ of choice,” Premsrirut added. “We can customize it beyond just having an inducible mouse.”

Such customization can include mouse models with complex genetics, which, for example, might be required for the study of diseases caused by multiple mutations, she said.

Traditionally, creating these kinds of mouse models requires cross breeding between animals each with a specific mutation. “That is a lengthy process that stretches out the time you need to develop a specific disease model,” Premsrirut said. Mirimus' proprietary method of embryonic stem cell derivation promises to shorten this timeline by months.

'Getting Big Pharma Interested'

Mirimus was founded in late 2010 after officials at NCI became aware of the work Lowe was conducting at CSHL and requested he develop embryonic stem cells for 1,500 mouse models, Premsrirut said. As a result of this contract, “we re-did the pipeline to enable high-throughput production of these stem cell lines.”

As this effort was advancing, investors familiar with the research being conducted at CSHL approached the institute about formally commercializing the mouse-model technology, and the company was formed. It closed a $2 million Series A round of financing in 2011, and remains housed at CSHL with approximately seven employees.

It has successfully attracted a number of academic customers, but has yet to achieve significant interest from industry, a situation Premsrirut attributes to the newness of the firm's technology.

“With so many technologies, there are so many ways of doing things,” she said. “It will take a little time [to] show … that mouse models are the way to go versus cell-based assays or doing transplant experiments in nude mice, which has been the traditional drug-development screening process.

“With all of the new technologies to develop mice directly from embryonic stem cells … it's catching on that there's another way to do this,” she added.

An important aspect of this process has been Mirimus' collaborative relationships with its academic clients, who are offered discounted services in exchange for data-sharing arrangements and help validating and optimizing the technology.

“Having the academics use the technology can show that this is feasible,” Premsrirut said. “And the more we're able to do, the more cost-effective it becomes, and that always plays a role in getting big pharma interested.”

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