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CS Genetics Cementing Patents, Preparing to Finance Circulating DNA Test Development

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NEW YORK (GenomeWeb) – Startup CS Genetics has begun the process of introducing what it believes is a novel and superior method for disease detection and assessment via circulating nucleic acids.

Though the company has not shared data publicly that demonstrates this, the firm believes it can develop tests to screen for early-stage cancers, as well as for other applications that would rely on tracking cell-free DNA to particular locations or origins in the body.

In an announcement last week, the company stated its intention to use a molecular indexing method it calls "coding strand sequencing," as well as proprietary methods for analyzing DNA and RNA in circulating microparticles, to develop a pan-cancer screening test and tools for clinical indications like non-invasive prenatal testing.

Lucas Edelman, the firm's founder and one of only two current employees, wrote in an email this week that he started the company in 2014 after receiving a PhD at the University of Cambridge, and has been in "stealth mode" for the last four years "developing and validating the key aspects of our technology and making … key patent filings to protect [the firm's] inventions."

The company hasn't released any data, but Edelman claimed that the results of its work so far are positive enough that it is now prepared to seek a "fairly large investment" later this year to begin to hire additional employees and start its next phase of product development.

So far, CS has been supported by private investors with the funds needed to support key proof-of-concept work and make foundational patent filings.

At the heart of the tests CS intends to develop is the coding strand sequencing method that Edelman said allows for indexing or barcoding of either single molecules, single cells, or single circulating microparticles: exosomes, extracellular vesicles, apoptotic bodies, and other clumps or bundles of nucleic acids in various sizes.

In his email, Edelman said that the coding strand technique, which is sequencing platform-agnostic, is akin to other molecular indexing approaches in some ways, and unique in others. The technology has two components, he said. The first is indexing reagents, which are "functionally similar to basically all other indexing reagents." 

"Each individual indexing reagent has a large number of barcodes that are used to tag and then identify target nucleic acids, for example from a single cell, [or single microparticle]" he wrote. Building from there, a library of many different indexing reagents, each with different barcodes, can then be used to tag and identify nucleic acids from a whole population of single cells or microparticles.

The second component is the firm's proprietary indexing reaction method, which does not require a sample to be separated into microfluidic partitions as in most current approaches.

Reagents and their targets (circulating microparticles in the case of the tests CS Genetics is developing) are mixed together into a single solution — "literally within a single sample tube" — Edelman wrote. In this way, the indexing reaction is performed directly, "without partitioning, and without the need for any complex microfluidic instrumentation or manipulation."

Interest in non-invasive cancer detection, as well as blood-based diagnosis of other diseases, has skyrocketed over the last two years, so CS Genetics is gearing up to enter an increasingly crowded and competitive field.

According to Edelman, though, most currently described methods are "molecule-based" or "cell-based" as opposed to "microparticle-based," in the case of what he hopes to achieve with his company.

"The key problem with cell-based liquid biopsy methods is that circulating tumour cells are at extremely low concentrations even at late metastatic stages, and essentially non-existent during early cancer stages. The obvious [challenge] with molecule-based liquid biopsy methods is that the cancer/genomic "signal" is irretrievably fragmented and scrambled: there is no way of knowing which cell or body tissue any given DNA, RNA, or protein molecule has come from," he wrote.

In CS Genetics' opinion, microparticles offer a biologic "sweet spot," marrying genomic content and physical concentration. Neither Edelman nor the company has published any of this research, but he claims that the firm has demonstrated that "individual circulating microparticles can contain thousands to millions of DNA molecules," and that "each milliliter of blood contains … a concentration [of particles] that is high enough to allow reliable detection … even [in] early-stage cancers through standard peripheral blood draws."

Some companies are already using, or hope to use, circulating microparticles like exosomes, to diagnose or analyse disease, including Exosome Diagnostics, which was recently acquired by Bio-Techne.

But Edelman said that his company's approach is distinct from these because it allows single-microparticle sequencing — where sequencing reads can be mapped back to a single specific microparticle — as opposed to analysis of all the nucleic acids extracted and pooled from a population of circulating particles.

According to CS Genetics, this ability to examine genetic and epigenetic features of single circulating microparticles, offers a novel and powerful source of information about not only the presence of cancer-associated mutations, but also the organ or tissue where it originated.

"Making these measurements across the extremely large number of individual microparticles present in a blood draw will give an extremely accurate, integrative … appraisal of health and disease throughout the body, similar to assessing thousands of small, invasive biopsies if they were taken across all of a patient's organs and tissues," he wrote.

Other companies and academic groups have been coming forward in recent months with epigenetic techniques to track blood-borne DNA back to specific sites of origin in the body, and Edelman said that CS Genetics has certainly benefitted from academic discoveries in this area that have been made public.

But he argued again that his company's approach — using coding strand sequencing to index individual microparticles across an entire blood sample — is distinct from methods that interrogate epigenetic changes without this ability to resolve data to individual microparticles.

The firm has not yet published any data on the approach, but Edelman said that CS is now starting preclinical development of a diagnostic assay that uses the highly parallel, single-microparticle DNA measurements he described. This assay will involve both genetic and epigenetic measurement of DNA from single circulating microparticles, across thousands to millions of microparticles simultaneously.

Moving forward, the firm will seek to demonstrate that it can use its techniques to create a diagnostic that can detect at least 90 percent of early-stage cancers with a false positive rate below one percent.

Non-invasive prenatal testing is also a target area, and Edelman said that the company expects to start major clinical trials in about two years, with early cancer detection applications following thereafter.

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