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NanoString Demos Sequencing Technology at AGBT With Sights Set on 2019 Launch

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NEW YORK (GenomeWeb) – At last week's Advances in Genome Biology and Technology meeting in Hollywood Beach, Florida, NanoString provided an update on its Hyb & Seq technology, including more details on the hybridization-based sequencing approach. The firm is targeting a 2019 launch, and expects to present customer data at the 2018 AGBT meeting.

At this year's AGBT meeting, the company had a prototype instrument and ran an 11-gene oncology panel on-site, starting from formalin-fixed paraffin-embedded tissue. Joe Beechem, senior vice president of research and development at NanoString, said that the prototype sequencing machine had been repurposed from its nCounter Sprint instrument.

NanoString is targeting the clinical market with its Hyb & Seq technology, and while it plans to have applications in a number of disease areas, an initial focus will be in oncology. One key to the technology is that it enables DNA extraction and target capture probes to be added in one single-tube step. In addition, the technology does not use enzymes or include an amplification step — two bottlenecks for sequencing in the clinic, according to Beechem.

Brad Gray, NanoString's CEO, said that the Hyb & Seq technology will fit "naturally" with the firm's other products. He added that targeted cancer sequencing will be one of the first applications, and he anticipates that "in the future, Hyb & Seq will be used right alongside our existing nCounter Dx FLEX systems," which has US Food and Drug Administration 510(k) clearance along with its Prosigna breast cancer prognostic gene signature assay.

He added that the technology would help expand the company's focus, rather than shift it to a completely different focus. In particular, he said the firm is interested in targeting clinical settings "that other sequencers cannot reach, such as small hospitals and even community oncology practices."

NanoString initially described the technology at last year's AGBT meeting, and while it is still a couple of years away from launching, the company has three prototype instruments that have been running in its lab for the last three months.

Beechem said that the Hyb & Seq technology is a natural extension of the company's core focus of optical barcode technology and clinical applications. However, NanoString has made some key changes to the optical barcode technology, he said. For instance, the company uses 2,000-nanometer optical barcodes in its digital biology technology, but for sequencing, it reduced them to between 20 and 50 nanometers. In addition, they are read out sequentially, rather than spatially, he said.

During an interview as well as two presentations, Beechem provided additional details about the technology. For example, sample prep happens in three steps. First, an FFPE curl is placed in a single tube where the DNA is extracted and target capture probes are added. The target capture probes "grab" a molecule of DNA, with one probe binding to the 3' end and another to the 5' end. The cellular debris is then removed via a syringe filter, and a bead purification step isolates the DNA targets from filtrate.

The sample prep takes one hour with 15 minutes of hands on time. The library is then loaded onto the flow cell. As a demonstration of its simplicity, NanoString recruited James Hadfield, head of genomics at Cancer Research UK, to perform sample prep and start a sequencing experiment in real-time during Beechem's lunch presentation.

The technology is a sequencing-by-hybridization scheme in which DNA or RNA is read 6 bases at a time through the use of a set of 4,096 hexamer barcodes. Each barcode contains a sequencing domain — a 6-base region complementary to the target molecule — as well as a barcode domain with three reporter regions: R1, R2, and R3. Each reporter region will bind a two-color reporter probe, which corresponds with two nucleotides. Thus, each 6-mer barcode is translated into the corresponding sequence two bases at a time.

Beechem said that the technology would enable both short and long reads as well as both DNA and RNA analysis. Each so-called "grabbed" region is anchored to the flow cell by the capture probes and is around 50 base pairs in length, Beechem explained. As sequencing occurs, fluorescent dots start popping up along a screen. Long reads are enabled when the fluorescent dots start lining up next to each other, since they indicate a contiguous stretch of DNA, Beechem said.

Currently, the error rate is around 2 percent on the first pass, but Beechem said that rereading the same base five times increases the single-base accuracy to 99.99 percent, a QV 40 quality score. 

Beechem said one goal of providing an update at this year's AGBT meeting was to spark conversations with researchers and industry about collaborating on developing the technology for various applications. Already, NanoString has reached out to Pavel Pevzner, professor of computer science and engineering at the University of California, San Diego, to develop an assembly algorithm for its data, Beechem said. Pevzner's group previously published SPAdes, for single-cell genome assembly.

Several analysts noted after the conference that NanoString's Hyb & Seq technology, as well as two other technologies it is developing, 3D Biology and Digital Spatial Profiling, could potentially drive growth of the company in the long term. They acknowledged, however, that it is too early to judge the sequencing technology and that there are a number of unknowns about the technology and how it will fare when commercialized.

For instance, while Stephane Budel, an analyst with DeciBio, was impressed with NanoString's Hyb & Seq technology, he speculated whether targeted oncology sequencing, was starting to become "crowded," particularly by Illumina and Thermo Fisher Scientific's Ion Torrent. "It will be interesting to see how NanoString decides to position the platform," he wrote.

Bryan Brokmeier, an analyst with Cantor Fitzgerald, wrote in a note following the AGBT meeting that although it was still early in development, the Hyb & Seq technology "may eventually be a competitive platform that uniquely can sequence both DNA and RNA simultaneously from the same sample, has a simple workflow, and offers both long and short reads, thereby competing with both [Illumina] and [Pacific Biosciences]."

Doug Schenkel, an analyst with investment bank Cowen and Company, noted that in addition to Hyb & Seq, NanoString's investments in the 3D Biology and Digital Spatial Profiling technologies would likely not have immediate consequences, but could be transformative for the company over the long term.

NanoString was a "tour de force … showcasing promising new product initiatives that could accelerate the long-term revenue growth trajectory of the business over the next few years," Schenkel wrote.

For instance, he said, although NanoString's current 3D Biology products account for only 5 percent of consumable sales, the products factor into 20 percent of nCounter system sales. "Accordingly, 3D Biology may be on the cusp of increasingly contributing to revenue growth," he said.

In particular, he added that the company seemed to be placing particular emphasis on Hyb & Seq, potentially investing around $50 million in its development.

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