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Boreal Genomics Scraps Liquid Biopsy Plans to Focus on Linked Molecule Technology


SAN FRANCISCO (GenomeWeb) – Boreal Genomics is no longer focused on developing cell-free DNA-based clinical oncology assays and has instead switched gears to focus on linked molecule technologies for targeted sequencing and to reduce sequencing errors, GenomeWeb as learned.

Recently, the firm described a new targeted sequencing sample prep method, called Linked Target Capture (LTC), in a study published in the journal PLOS One.

"We've now focused the entire company on this technology development," said Andre Marziali, Boreal's founder and CSO. "This will be the core of what we do."

The company currently has an early-access program for the technology and Marziali said that it is in discussions with potential partners about commercialization, although he did not have a timeline. "We won't be offering the kit ourselves but will partner for commercialization," he said.

LTC is a target enrichment sample prep technique that uses physically linked capture probes and primers to select and amplify targets. The technology aims to combine the best of amplicon-based sample prep and hybrid capture, according to Joel Pel, Boreal's head of technology development.

The way it works is that universal primers are connected to the target hybridization probe at the 5' end. When the hybridization probe binds to its target, that also brings the universal primer into close proximity to the priming site on the template molecule, enabling selective amplification of the target molecule.

The advantage of this method is that it speeds up the process, Pel said, reducing target capture to under eight hours from several days.

To test the workflow, the Boreal team designed probes to target 35 cancer-related genes and tested the panel on DNA from cell lines, formalin-fixed paraffin-embedded tissue,  and cell-free samples.

They found that for all sample types, the on-target rate was between 86 percent and 97 percent and uniformity was between 90 percent and 96 percent. They noted that on-target rates of commercially available kits typically range from 75 percent to 87 percent.

In addition, the Boreal team combined the linked target capture scheme with unique molecular identifiers in order to detect low-frequency variants. In the study, the researchers used four-base UMIs integrated into the ligation adapter andtested the panel on a cell line with known variant frequencies.

The researchers detected all variants at frequencies within three-fold of the expected values, down to a frequency of 0.25 percent. At that level, however, accuracy dropped, missing four of the 12 variants in the 0.25 percent to 0.56 percent range. However,  at frequencies between 2.5 percent and 5.6 percent, they were able to detect all 12 of those same variants, which included SNVs, indels, and fusions. In addition, the panel correctly called all wild-type variants.

Boreal originally began developing linked molecule technologies as part of its work to develop liquid biopsy assays. Last year, the firm described a technique called Pro-Seq for increasing the accuracy of sequencing and improving the detection of low frequency mutations. That method involves linking the two strands of a double-stranded DNA fragment in order to detect sequencing errors  by comparing the sequence of the two strands of the DNA molecule.

LTC and Pro-Seq are fundamentally different technologies, Marziali said. Pro-Seq is designed to reduce next-generation sequencing errors without relying on UMIs, while LTC is designed as an alternative to other commercially available target capture technologies, like Thermo Fisher Scientific's AmpliSeq or Agilent's SureSelect. In addition, Pro-Seq and LTC could be complementary and he said that Boreal is working on combining them.

While developing Pro-Seq, the Boreal researchers also began exploring linked molecule technologies for other applications, and when they developed the LTC technology, the company "realized that we had something on our hands that could have a much more immediate impact" than developing oncology assays, Marziali said. He noted that target capture and sample prep is currently a bottleneck in NGS workflows, with most technologies taking several days. With a workflow of under eight hours, LTC could fill a need, particularly in clinical applications where turnaround time is important, he added.

Separately, Boreal was involved in a pilot study to test the ability of the cfDNA technology it had been developing to detect cancer in asymptomatic individuals. Marziali said that the trial is ongoing and almost complete but noted that because it was based on technology that the firm is no longer pursuing, it is unlikely to be relevant to Boreal's future endeavors.

Boreal had previously been developing cell-free DNA technology and in 2016 struck a deal with Trovagene to merge the companies' technologies and codevelop assays to detect circulating tumor DNA.

The company is no longer pursuing these applications, though. "We are really focused on the linked molecule technology," Marziali said.