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Twistnostics Using Phase II NIH Grant to Develop Circulating DNA Mutation Assay

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NEW YORK (GenomeWeb) — Twistnostics this month was awarded $212,371 from the National Cancer Institute to support the second year of its project to develop an assay for detecting cancer mutations in circulating DNA in body fluids such as blood and urine.

Twistnostics has previously hinted at the possibility of harnessing its PCR-free, array-based technology for cancer detection in addition to the infectious disease diagnostic and pharmacogenomic applications it has been pursuing, but had not previously detailed its intentions in oncology.

The company's CEO Alfredo Celedon told BioArray News that it hopes the renewed funding for its cancer mutation detection project will enable it to adapt its platform for the early detection of cancer biomakers in circulating DNA in blood or other body fluids.

Efforts to advance technologies for detecting cell-free DNA or circulating tumor cells for cancer diagnosis, treatment monitoring, or other health interventions have exploded in recent years, but Twistnostics believe its technology can offer an advantage in sensitivity, simplicity, and cost-effectiveness.

"We want to demonstrate that we can detect cancer-associated mutations in body fluids, particularly blood and urine, without PCR amplification," Celedon explained.

Because mutated cancer DNA molecules are present at low concentration and in the background of a lot of wild-type DNA, he said, detection technologies have to be supremely sensitive and have a low error rate.

"In most approaches that are currently being used for detection of mutations in body fluid, there is a PCR step, which by itself introduces mutations, so it's really a bottleneck in the field of analyzing cell-free DNA," he said. "You always have the error rate of the polymerase as your limiting factor in your capacity to detect."

Moreover, according to Celedon, even approaches that are highly sensitive despite the use of PCR — such as Sysmex's emulsion-based digital PCR technology, BEAMing — are difficult to multiplex without significant added time and cost.

In its NCI-funded project, as a proof of concept Twistnostics plans to demonstrate that its technology can detect KRAS mutations in cell-free DNA from urine and plasma of early-stage pancreatic cancer patients. In addition, according to its grant abstract, Twistnostics hopes the pilot will show that its Twist-Biosensor microarrays are "faster and require fewer steps than alternative diagnostic techniques."

Twistnostics' core technology is its Twist-Biosensor, which relies on DNA supercoiling to convert the nucleic acid hybridization of a single DNA molecule into a mechanical signal that can be detected using standard semiconductors. As the bound targets are subjected to disrupting torsional stress, the rate of detection is increased and background noise is reduced. According to the company's project abstract, the single-molecule detection capabilities of the Twist-Biosensor makes the technique ideal for detection of mutated DNA at low concentration compared to prevalent wild-type DNA.

For now, Celedon said, the company is not trying to multiplex highly. In the pilot, the researchers are only going to look at detecting about 10 or fewer KRAS mutations.

But if this initial work is successful, the plan would be to try to develop panels of about 20 mutations each, specific for different cancers. These would be intended to serve as screening tools for early cancer detection.

In the effort, Celedon said Twistnostics is working with two clinical collaborators at Johns Hopkins University, Michael Goggins and Christopher Gocke, to help direct its experiments and provide patient samples.

Other assays

Beyond this cancer detection project, Celedon said Twisnostics has also made progress recently in its efforts to develop a pharmacogenomic assay.

While the company has already shown it can detect a panel of PGx polymorphisms in about three hours, Twistnostics wants its test to work within the even smaller timeframe of a typical doctor's office visit.

"We believe the test needs to be done while the patient is in the office," Celedon said. "There are several techniques already available that take a few hours, but we think this is impractical from the point of view of a patient that goes to a doctor and needs to be medicated, to then have to go home and wait for an answer."

To do this, the company is working on adapting its PGx assay to work without PCR amplification, much like its cancer diagnostic project.

Both the PGx panel and the circulating cancer mutation project are moving more slowly toward commercialization than Twistnostics' infectious disease diagnosis work, Celedon added.

Its drug-resistant gram-negative bacteria test and other assays in the works in the infectious disease space will most likely be the first to market, he said, although he did not provide a detailed timeline.

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