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Exosome Diagnostics Investigates NGS for Diagnostic Tests in Biofluids

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This article has been updated to clarify Exosome's partnerships.

Exosome Diagnostics is exploring next-generation sequencing as a potential platform for diagnostic tests for cancer and other diseases in biofluids.

The company was founded in 2008 around exosome technology it exclusively licensed from Massachusetts General Hospital. While Exosome currently focuses on developing qPCR-based diagnostics for prostate and brain cancer, it has also been investigating next-gen sequencing and recently brought in the Illumina MiSeq platform.

The company's core technology applies to exosomes, lipid microvesicles containing nucleic acids and other molecules that cells shed into bodily fluids such as urine, cerebrospinal fluid, and blood. The firm has extensive expertise and IP around isolating exosomes from biofluids and extracting and analyzing their RNA and DNA content. "The key to the technology is that we are able to enrich for a very highly purified, stable form of RNA in fluid," CEO James McCullough told Clinical Sequencing News.

In 2008, Johan Skog, Exosome's director of research, while at MGH, published a study in which he and his colleagues detected tumor-specific RNA variants from serum microvesicles of glioblastoma patients, suggesting a potential use of exosomes for diagnostic biomarkers. A year later, Skog and a team of Swedish researchers published another study on the possible use of urine exosome-derived biomarkers in prostate cancer.

Exosome raised $20 million in a Series A round in 2010 that was co-led by NGN Capital, which is based in New York and Heidelberg, Germany, and Forbion Capital Partners, located in Naarden in the Netherlands and in Munich, to develop and commercialize exosome-based cancer diagnostics.

According to McCullough, one of the requirements of the financing was to establish a presence in Europe, so besides its research laboratory and corporate office in New York, the company opened a research subsidiary in Martinsried near Munich in 2010, now the firm's DNA sequencing laboratory. Also in 2010, it added a laboratory in St. Paul, Minn., which has become GMP-compliant and was CLIA-certified earlier this year, as well as a small manufacturing facility.

Across its three locations, the firm has more than 30 employees. It is currently conducting a multi-million Series B financing round, which it hopes to close this summer.

Exosome is working on a series of exosome RNA-based diagnostic tests for prostate cancer, with additional tests for brain cancer to follow. The goal is to develop FDA-approved in vitro diagnostic tests, and the company has clinical studies for both tumor types underway.

The firm plans to eventually add other disease areas and is already conducting a study in Alzheimer's.

According to McCullough, the advantage of analyzing exosomes over, for example, circulating tumor cells or free DNA is that the RNA they contain is stable, and the information is very sensitive and specific. "It's very important that you have a stable source of RNA that you can isolate, and we believe one of the only ways to do that is through the exosome," he told Clinical Sequencing News.

Partnerships are allowing the company to conduct clinical studies. Last fall, Exosome entered a multi-year collaboration with the Prostate Cancer Foundation to clinically validate its technology in prostate cancer, studying disease-specific RNA in exosomes from blood and urine. According to McCullough, it also enables the company to conduct a clinical study with about 20 centers that will include a geographically diverse patient population.

Earlier this year, Exosome also announced a collaboration with the foundation Accelerate Brain Cancer Cure to validate its technology clinically in glioma, which McCullough said is allowing it to pursue a multi-center clinical study. The partners said at the time that they will explore the technology for progression monitoring and advanced disease risk stratification in glioma.

One reason the company is focusing on prostate and brain cancer, McCullough said, is that urine and cerebrospinal fluid are easier to study than blood, and that urine in particular can be quickly and inexpensively obtained for clinical studies. "We're rapidly catching up on the blood, but starting in CSF and urine was an easier approach for the technology than starting in the blood, which is highly complex," he said.

In addition, the company is seeking to partner with a large instrument manufacturer, "which will give us the ability to put our biofluid diagnostics in hospital laboratories around the world," he said.

"Our strategy is to continue to partner with best-in-class manufacturers, clinicians, all of the people that you need to put out a successful molecular diagnostic, and we intend to pursue a full-blown IVD strategy for regulatory kits," he said.

The company expects to obtain results from its clinical studies toward the end of his year and in early 2013. The aim is to launch tests first through its St. Paul-based CLIA laboratory next year, followed by the submission of clinical IVDs to the FDA, also in 2013.

McCullough declined to provide details about the clinical trials at this time, noting that the company plans to present data from the studies at several upcoming scientific conferences this year and next, starting with the American Urological Association annual meeting this month.

Exploring Sequencing

While Exosome is currently developing its commercial tests on a qPCR platform, it is already exploring next-generation sequencing as a possible alternative and recently installed the Illumina MiSeq platform at its Martinsried laboratory.

It has also been collaborating on sequencing projects, for example with John Quackenbush at the Center for Cancer Computational Biology at the Dana-Farber Cancer Institute, which has an Illumina HiSeq; and it has outsourced sequencing to commercial service providers such as GATC Biotech.

The company has developed a multiplexed sequencing method for mRNA from blood and urine exosome preparations that allows it to detect rare mutations with high sensitivity, and to interrogate hundreds of mutations simultaneously.

It currently uses a targeted sequencing strategy, analyzing panels of tens of PCR-amplified cDNAs that are derived from exosome RNA.

According to Mikkel Noerholm, the company's director of European operations, sequencing provides vastly more information than qPCR and allows researchers to combine targets more flexibly. "You can combine different mutations, targets you're looking for, in a mix-and-match way, depending on what you're looking for," he said. "If it's melanoma or lung cancer or colorectal cancer, there will be a different subset of mutations that will be relevant for that particular disease."

Earlier this year, Exosome and the department of dermatology at the Ludwig Maximilians University Munich won a €1 million ($1.3 million) grant from the German government to develop exosome-based diagnostic tests for malignant melanoma, a project that the partners said will use both next-generation sequencing and qPCR.

For this study, the researchers are using exosome sequencing to determine the mutational status of patients, to look for resistance mutations occurring during treatment with targeted inhibitors, and "other applications where it would be beneficial to have longitudinal sampling … which if course is not really feasible if you need tissue every time," Noerholm said.

Initially, Exosome will likely commercialize next-generation sequencing-based assays as a service to researchers wanting to analyze cohorts of clinical samples, he said.

"The next stage would be to offer tests through the CLIA facility as laboratory-developed tests, and then of course, eventually, possibly as an FDA-cleared test," he said. While that is still farther off in the future, he added, "it's extremely important to grow with the technology."

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