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Qiagen Launches 'Digital NGS' Products Based on Molecular Indexing Technology


NEW YORK (GenomeWeb) – Qiagen last week launched a portfolio of next-generation sequencing panels and a custom panel design service based on a proprietary digital barcoding technology that the company claims enables unbiased, accurate quantification of DNA, RNA, and miRNA on essentially any sequencing platform.

The QIAseq panels, which are available now, are the first of three product launches Qiagen has planned for the second half of the year. In addition, the company plans to launch the PAXgene product for collecting, stabilizing, and purifying cell-free DNA from blood samples for liquid biopsy applications; and QIASeq single-cell library kits for PCR-free, next-generation sequencing-based analysis of DNA and RNA from single cells.

Each of these product launches represents a greater than $100 million market opportunity, Qiagen CEO Peer Schatz said during a conference call last week recapping the company's second quarter earnings. In Q2, Qiagen reported a 5 percent year-over-year spike in revenues while beating analyst estimates on the top and bottom lines.

During the call, Schatz noted that existing solutions for NGS panel design are "far from perfect."

"The efficiency and effectiveness of the current workflows have been hampered by problems in the early workflow stages such as the formation of PCR duplicates during amplification and also general amplification bias due to non-uniform PCR reactions," Schatz said.

These issues, he added, are addressed through Qiagen's new "molecular indexing" technology, in which molecular indices or barcodes are attached to discrete DNA molecules during an initial target enrichment step. These labels can then be recognized at a later stage in reference to the original target DNA molecules, and specific indices "can be quantified with maximum high-resolution power," Schatz said.

Further detailing the technology in a follow-up interview with GenomeWeb, Brad Crutchfield, senior vice president of life sciences at Qiagen, noted that it also uses a single-primer extension step that gives the workflow unique advantages.

"In the simplest sense, you capture that molecule early on in the workflow; you label it; and then the single-primer extension [gives you] the ability to work essentially across the entire genome," Crutchfield said. "We look at this product as something where you can sequence the unsequenceable. [Many] other technologies require essentially dual-capture probes, so you've got to know exactly where you're going, and that really makes it difficult for certain parts of the genome to be sequenced in a panel-based way."

The barcoding step also vastly improves signal-to-noise ratio, "and that allows you to create highly sensitive assays that, without this, couldn't be done." Crutchfield said that QIAseq panels should regularly boast a mutation-detection sensitivity of about 1 percent, although with the potential to reach a sensitivity of around 0.1 percent for smaller and very targeted panels.

Crutchfield said that Qiagen developed the molecular indexing technology in house, although the company is not the first to employ such a strategy for targeted NGS. Last year, San Francisco Bay area firm Cellular Research, whose founders include Stephen Fodor, Glenn Fu, and Stephen Quake, debuted its Pixel gene expression profiling platform based on a similar technology with the exact same name — molecular indexing. In addition, Cellular Research said it planned to launch a massively parallel single-cell RNA sequencing method based on the technology some time this year.

In addition, last month researchers from New York University described a method for detecting very rare mutations in a population of cells using an error-corrected sequencing approach called maximum-depth sequencing, which adds barcode and adaptor sequences directly onto a short sequence of interest so it can be amplified and sequenced many times in parallel to produce a consensus sequence.

Qiagen's Crutchfield noted that the differentiating factor with the Qiagen product is the nature of the barcode chemistry, and in particular the single-primer extension step, "which gives a lot more flexibility in the way the panel is designed."

Qiagen is launching four QIAseq products leveraging the technology: QIAseq targeted DNA panels to detect low-frequency gene variants and access challenging genomic regions including GC-rich areas; targeted RNAscan panels for sequencing RNA-derived libraries for sensitive, quantitative detection of known and novel gene fusions; miRNA NGS kits, which specifically address the problems of contamination by unwanted sequencing reads common to this application; and targeted RNAseq kits for gene expression studies of up to 1,000 targets from as little as 10 nanograms of RNA input.

The kits are platform-agnostic, and as such can be run on essentially any commercial sequencing platform, with the most validation work having been completed so far on Illumina platforms, Crutchfield said. "Our microRNA ... panel does not work on the [Thermo Fisher Scientific] Ion Torrent, and it has to do with some read length issues, but our other panels do," he noted.

Besides the kits, Qiagen is also offering a custom panel design service, which has the advantage of tapping into Qiagen's pre-validated content covering more than 60,000 gene targets. Furthermore, Qiagen plans to incorporate the molecular indexing technology into its own NGS panels for the GeneReader sequencing platform, which has been commercially launched but will have four new panels associated with it in the near future: the QIAact Breast Panel and QIAact Lung Panel, both set to launch by the end of this year; and the QIAact Onco-Heme Panel and Gene Expression Signatures Panel, both expected to be ready for market in 2017.

Qiagen's new NGS kits have already been validated on both formalin-fixed, paraffin-embedded tissue samples and liquid biopsy samples, including circulating tumor cell and cell-free DNA samples.

Although the molecular indexing technology is extremely useful for FFPE samples, where genomic content is often scarce or degraded, the liquid biopsy piece is where Qiagen, like many other companies, sees a real need for innovative NGS technologies, and this dovetails into the other two major product launches Qiagen is planning in the second half of this year.

With its forthcoming PAXGene blood system for cell-free DNA, "we want to replicate the great successes we've had with the PAXGene Blood RNAse and DNAase systems, as well as the tissue RNA solutions," Schatz said during the earnings call last week.

"The cell-free DNA solution is a breakthrough for customers involved in prenatal testing and cancer research," he said. "We have drawn upon our deep expertise to deliver an innovation that is essential but not easy to create, and that is to integrate the process for collecting the blood sample with the process of stabilizing cell-free DNA circulating in the blood in order to ensure unbiased and targeted DNA purification."

Finally, the company will join the scrum for single-cell NGS analysis. "The challenges here are rooted in the limited amount of sample material and data that can currently be generated," Schatz said. "We are launching new and completely PCR-free workflows for use with DNA and RNA that start with the cell and go through to the DNA library step for use on any NGS platform. These kits leverage a unique multiplication method and an efficient library construction technology to prepare highly accurate sequencing."

The company did not provide a more specific timeline for the launch of these products.

"We continue to evolve our sample technology product line around cell-free DNA, circulating tumor cells, and all aspects ... of liquid biopsy samples," Crutchfield concluded. "What we've really done is developed a comprehensive series of library prep products for whole-genome and whole-transcriptome sequencing. Right now, we feel we have the most comprehensive and technologically differentiated solution for NGS, from sample to insight."