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Keck Graduate Institute-led Team Begins New NIH Grant to Develop Point-of-Care Tuberculosis MDx

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NEW YORK (GenomeWeb) — A public-private team led by researchers at the Keck Graduate Institute of Life Sciences has been awarded just over $600,000 by the National Institutes of Health for the first year of a four-year project to further develop its point-of-care nucleic acid testing platform for tuberculosis diagnosis.

The new grant, administered by the National Institute of Allergy and Infectious Diseases, builds upon previously awarded similar grants and ongoing efforts by the same team of investigators to build a novel rapid sample prep module that is specially designed to handle the difficult-to-work-with sputum samples typical in TB diagnosis.

However, in the new project the team — which has previously included collaborators at sample prep firm Claremont Biosolutions — will also work with clinical researchers from the University of Washington and the Keck School of Medicine at the University of Southern California to begin validating the system with the goal of eventually obtaining regulatory approval for market release as an in vitro diagnostic, according to a recently published grant abstract.

The new project, the researchers wrote in their abstract, aims to enable diagnosis of pulmonary tuberculosis at the point of care in low-resource, high-burden countries with a portable, easy-to-use, nucleic acid testing device that integrates sample preparation, isothermal DNA amplification, and lateral flow-based detection without user intervention. In addition, they wrote, the final device is envisioned to provide a result in less than 1.5 hours from the time sample is loaded into it, and at a "significantly lower cost than currently available with fully integrated benchtop systems."

The principal investigator on the new grant is Angelika Niemz, a professor and director of research at KGI. In 2012 Niemz gave a presentation on her group's efforts to that point to develop the TB diagnostic, focusing primarily on what she deemed perhaps the most crucial component — a universal sample-prep cartridge featuring mechanical cell lysis and other technologies originally conceived of at KGI and licensed in 2008 to Claremont Bio, which has since further refined them into commercial products.

Niemz was also PI on two previous NIH grants, one that ran through June 2012 and supported development of a similar integrated device to enable rapid diagnosis of herpes simplex viruses I and II in STD clinics and maternity wards; and one that is set to run through June of next year and is also related to developing a point-of-care nucleic acid testing platform for TB.

The previously awarded TB grant proposed a device based on an isothermal amplification technology called exponential amplification reaction (EXPAR). Originally developed by KGI scientists and described in the Proceedings of the National Academy of Sciences in 2003, EXPAR is a fast isothermal reaction that uses nicking enzymes to cut recognition sites adjacent to a particular target to achieve target-specific amplification in minutes at a constant temperature of around 60° C.

Under the new grant, however, the team proposes using a different isothermal amplification technology called cross-priming amplification. This technology, which was developed at Chinese biotech firm Ustar Biotechnologies, uses five to eight cross-linked primers to amplify a DNA or RNA target sequence at a constant temperature. Researchers from Ustar and collaborating Chinese academic institutions described the technology in a 2012 Nature Scientific Reports paper, and previously validated the method for rapid detection of Mycobacterium tuberculosis from sputum samples in a 2008 Journal of Clinical Microbiology study.

According to the Keck team's new grant abstract, the group has now successfully designed and built a prototype integrated cartridge and instrument, and has demonstrated that the sample preparation, amplification, and detection subunits are functional.

Currently, the researchers are attempting to demonstrate fully automated execution of the various processes in an alpha prototype system, and the new funding will allow them to subsequently further develop and validate the system. This will include improving the thermal stability of master mix reagents, refining on-board reagent storage, incorporating a lateral flow strip reader, and ensuring overall system robustness, according to the grant abstract.

Then the researchers hope to refine the design of their device for manufacturability and scale-up manufacturing to produce a sufficient number of cartridges and instruments to analytically and clinically validate the system.

"These three aims will culminate in [an] application for CE-IVD regulatory approval, to enable market entry," the researchers wrote. The group's final goal will be to "develop a docking station to which four of the portable instrument units can be attached, as an upgrade to the basic system. This docking station will provide enhanced quality control, a better user interface, plus wireless connectivity, enabling external quality assurance and electronic result transmission, two important operational aspects of disseminated TB diagnostics in low-resource, near-patient settings."

Claremont Bio will continue to collaborate with the Keck lab on development of the TB test, even as it develops its own sample prep and molecular diagnostic products based on many of the same core technologies.

For instance, in 2012 Claremont was awarded a three-year, $3 million grant from NIAID for continued development of its portable point-of-care assay system to detect Clostridium difficile infections and contamination.

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