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Sygnis Raises $3.6M; Develops New Polymerase to Amplify, Sequence Difficult Samples

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German-Spanish biotech firm Sygnis is making strides in its efforts to become a pure-play provider of DNA amplification and sequencing tools.

First, in late October the firm completed a rights offering and private placement of more than 1 million shares of stock, garnering gross proceeds of €2.7 million ($3.6 million), which it will use to further execute its new business plan and attempt to reach the break-even point by next year.

In addition, a team led by researchers from the Consejo Superior de Investigaciones Cientificas, or CSIC, in Madrid, has published a study detailing the discovery and characterizing PrimPol, a new type of human DNA polymerase to which Sygnis owns the rights.

Sygnis believes that the new polymerase will allow researchers to more easily amplify damaged DNA from difficult samples such as formalin-fixed paraffin-embedded tissue and forensic samples. As such, Sygnis is currently exploring use of the enzyme in PCR-based sequencing methods, and is seeking licensing partners for various other applications, according to a company executive.

Sygnis, which is traded on the German Stock Exchange under the symbol LIO1, formed in 2012 after German pharmaceutical company Sygnis Pharma merged with Spain's X-Pol Biotech, then a subsidiary of incubator and holding company Genetrix.

X-Pol had been founded in 2008 by Genetrix and Luis Blanco, a professor at CSIC and one of the inventors of QualiPhi, the company's first DNA polymerase technology and now the flagship product from Sygnis. Studies have shown that QualiPhi can increase the performance of DNA amplification, particularly of large DNA fragments and complete genomes, and enables a wide range of other applications including DNA amplification, repair, and modification of genetic targets of research and clinical interest.

Blanco, who is now a scientific advisor to Sygnis, also contributed to the development of the new PrimPol enzyme, which he and colleagues detailed in a paper published in October in Molecular Cell.

Specifically, they found that PrimPol is present in both nuclear and mitochondrial DNA compartments, and has the ability to start DNA chains with deoxynucleotides, unlike regular primases, which exclusively use ribonucleotides. Moreover, PrimPol is also tailored to bypass the most common oxidative lesions in DNA, such as abasic sites and 8-oxoguanine, according to the study's abstract.

"The principal novelties of PrimPol as opposed to QualiPhi and all other commercially used polymerases are the capacity of synthesizing its own primer (hence the name PrimPol from primase/polymerase) and therefore being able to amplify DNA without needing the external addition of random primers," Gabriel Márquez, vice president of new technologies at Sygnis, told PCR Insider in an email. "Secondly, PrimPol’s high tolerance against damaged (e.g. oxidized) DNA sequences … enables amplification of DNA samples that were hitherto difficult or impossible to amplify," such as FFPE or forensic material, Márquez added.

Sygnis believes that one of the most promising applications of the polymerase is in DNA sequencing. PrimPol can start reading and copying DNA without the need of random primers, which are required by all other commercially available enzymes and can bias amplification and sequencing results, the company explained. The polymerase function of PrimPol displays a high specific activity and is very efficient when copying DNA with different lesions.

The company is currently exploring the possibility of exploiting PrimPol’s high tolerance for template damages to amplify damaged DNA in thermocycling protocols and "as a novel sequencing enzyme because it has less incorporation bias for modified nucleotides (e.g. fluorescent nucleotides) used in many sequencing platforms," Márquez said.

Sygnis is also developing a new thermostable version of the enzyme, which is expected to expand its range of applications.

"We have identified and cloned from Thermus thermophilus a thermostable version of PrimPol that has the obvious advantage of being tolerant to high temperatures and can therefore be used in thermocycling applications where DNA is denatured at high temperatures," Márquez said.

The thermostable version of the enzyme could also be useful in "complex reactions where many enzymes are present [and] researchers often like to inactivate other enzymes without damaging the polymerase," Márquez added. "This would be possible here through heat inactivation of other enzymes but not PrimPol."

The thermostable version of PrimPol is, in other respects, "very similar" to the enzyme described in Molecular Cell, and patent protection is pending, he said.

Sygnis is also exploring out-licensing the enzyme for use in the aforementioned and other various applications. Sygnis has an established relationship with Qiagen, with X-Pol having previously granted Qiagen exclusive worldwide rights to the QualiPhi enzyme (PCR Insider 7/19/2012), and Sygnis later giving Qiagen the rights to distribute an amplification buffer for isothermal amplification (PCR Insider 5/16/2013).

In a statement, Syngis noted that the new Molecular Cell publication is expected to catalyze "a lucrative licensing agreement [in the coming months] with a multinational leader in the field of DNA amplification and next-generation sequencing."

Márquez additionally told PCR Insider that Qiagen indeed could be a candidate to license the new PrimPol enzyme, but that Sygnis is "also exploring possibilities of partnering with other interested parties. So far, the general interest in the enzyme is high, and a number of companies have already received enzyme samples for their internal testing," he added.

To support these and other endeavors, Syngis will use the recent €2.7 million cash influx, which it raised by offering 1,019,309 new shares of stock at €2.65 per share to existing shareholders and select German and international institutional investors.

"The transaction is in our view in the best interest of the company and its shareholders as it provides the company with the financial flexibility needed to further execute on its business plans and closes the gap to break-even expected in 2014," Sygnis CEO and CFO Pilar de la Huerta said in a statement.

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