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With US Patent in Hand, TGen, NAU Seek Commercial Conduit for H1N1 Flu Assay

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NEW YORK (GenomeWeb) — The Translational Genomics Research Institute and Northern Arizona University have been jointly awarded a US patent for an allele-specific, real-time PCR-based assay to detect H1N1 pandemic flu and resistance to antiviral treatments.

With the patent in hand, TGen and NAU are now seeking a commercial partner to bring the assay to market, where it may prove useful in diagnosing H1N1 flu and determining whether it is resistant to commonly used antiviral treatments such as adamantane derivatives and oseltamivir, marketed as Tamiflu by Roche.

The patent, US No. 8,808,993 and entitled "Methods and kits to detect new H1N1 swine flu variants," was initially developed in 2009 by scientists at TGen's Pathogen Genomics Division (TGen North) in Flagstaff, Ariz., in response to the global H1N1 flu outbreak that year.

Several real-time PCR assays for H1N1 exist and many were granted emergency use authorization by the US Food and Drug Administration in 2009. A TGen spinoff company, PathoGene, was tasked with bringing the TGen and NAU assay through the EUA process, but ultimately fell short due to timing issues. PathoGene has since been acquired by DxNA, which already had its own influenza MDx intellectual property, so the IP rights to the H1N1 test fell back to TGen and NAU.

However, in light of an uptick in recent years of flu virus resistance to commonly prescribed antiviral medications, the TGen/NAU test may ultimately prove to be more useful than any of the 2009 EUA assays for future pandemics or even for routine flu diagnosis.

"The most significant clinical impact is putting antiviral resistance information in the hands of treating clinicians, much like we do for antibiotic resistance for bacterial infections," David Engelthaler, director of TGen North and one of the inventors of the new flu assay, told PCR Insider in an email.

"We hope to shift the current paradigm of clinicians using antivirals without resistance testing, [and] basing their decision on whether or not they've heard any info from the health department on the level of antiviral resistance in the community," Engelthaler added. "Hopefully this assay can be validated and approved for use on any number of real-time PCR instruments, which are becoming commonplace in the clinical setting."

The new assay achieves its specificity for both viral and antiviral-resistance markers through the use of mismatch amplification mutation assay PCR (MAMA-PCR), a modified allele-specific real-time PCR technique that was originally described by a different research team in the early 1990s.

"Essentially the use of real-time PCR allows for the clear discrimination of amplicons that are nearly identical," Engelthaler said. "Since there are well-established individual SNP alleles for each of the targets (H1N1-p09, and drug resistance to adamantanes and oseltamivir), the primer set includes a primer for each allele, for each target, and determines [the] presence (matched primer) or absence (mismatched primer) based on the resulting amplification."

Engelthaler added that "having only one probe for each target makes it cheaper than other SNP detection real-time PCR assays that typically have a probe for each allele (i.e., two per target). The primers can also be used in a number of ways, including other PCR approaches or for amplicon sequencing."

Although the 2009 swine flu epidemic was eventually curtailed, H1N1 "unfortunately is still a dominant flu strain seen around the world," Engelthaler said. Right off the bat the strain showed resistance to adamantanes, rendering them useless for H1N1 treatment.

Tamiflu resistance is less of a problem. According to US Centers for Disease Control guidance on antiviral drug resistance among influenza viruses, "sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, including with rare episodes of limited transmission, but the public health impact has been limited to date. However, additional sporadic cases of oseltamivir-resistant 2009 H1N1 virus infection can be expected, and ongoing surveillance for oseltamivir resistance among influenza viruses is essential for public health because oseltamivir is the most widely used antiviral medication."

And, according to the CDC, seasonal influenza A strains have also shown frequent resistance to adamantanes and sporadic resistance to oseltamivir and other antivirals like zanamivir. Thus, the new TGen-NAU assay could eventually be useful for routine flu diagnosis in addition to potential H1N1 pandemics.

Engelthaler said that TGen is "actively interacting with biotech partners to further the translation of the assay," but declined to provide further details on that effort.

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