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Harvard, Mass General Developing Exosome-Based POC Biomarker Test


NEW YORK (360Dx) – Researchers at Harvard Medical School and the Massachusetts General Hospital Center for Systems Biology are developing a point-of-care, exosome marker-based diagnostic test that can differentiate cancer exosomes from normal exosomes, a bottleneck that has slowed development of the technology.

Researchers see the clinical potential in exosomes — tiny vesicles shed by all kinds of cells, including tumor cells. They float around in blood and urine so systems can capture them for liquid biopsy-based cancer testing. However, trying to isolate tumor-derived exosomes and separate them from normal exosomes has slowed efforts to develop clinical tests.

Lead investigator Hakho Lee said in an interview that the test developed by his group at the Center for Systems Biology, the integrated magnetic-electrochemical exosome test, or iMEX for short, could be ready for licensing in around a year.

It integrates both vesicle isolation and detection into a single platform, and eliminates the need for ultracentrifugation that can take more than six hours in preparing exosomes for testing. A magnetic bead coated with antibodies enables the iMEX system to attract and isolate cancer-specific exosomes, and miniature electromagnetic sensors detect and identify the exosome-based proteins.

The group has reported in a paper published in ACS Nano that iMEX was able to detect exosomes at high levels of sensitivity. 

Lee said that his team is working to further improve the platform’s sensitivity, and will then conduct internal trials to prove its clinical utility.

The group has applied the test to screen for extracellular vesicles in plasma samples from ovarian cancer patients. It enabled simultaneous profiling of multiple protein markers within an hour, and outperformed "conventional methods in assay sensitivity and speed," the team reported.

The iMEX system currently provides eight concurrent measurements for exosome-based protein biomarkers, and the research group is exploring using the platform to identify exosomes that carry nucleic acids, including microRNA, which along with exosomal proteins would provide a more accurate snapshot of tumor states, Lee said.

The research group is developing the platform in Lee’s lab alongside a second exosome-based diagnostic test, nPLEX, which is suitable for high-volume applications and was licensed in December by Exosome Diagnostics, a firm that’s already offering exosome-based laboratory developed tests for lung and prostate cancer conducted in a CLIA-certified laboratory.

The firm is adding to its product portfolio with nPLEX and is working on device fabrication and scale-up for manufacturing, Lee said.

His high-throughput nPLEX test uses optical transmission through periodic nanohole arrays that function as sensors for exosomes. The sensor probe depth, of less than 200 nanometers, is matched to the exosome size to improve the test's sensitivity, and optical components provide detection and signal transmission. The approach enables fabricating-packed sensing arrays, Lee said, adding that the device has been optimized for use by large laboratories or large pharmaceutical companies that are developing anti-cancer drugs.

The device is suited to conducting massively parallel exosome screening, Lee said, adding that it has high detection sensitivity, down to the equivalent of 103 exosomes, and has greater than 1,000 detection sites.

In a paper published in the journal Nature Biotechnology, Lee and his colleagues reported using nPLEX to analyze ascites samples from ovarian cancer patients, and found that exosomes derived from ovarian cancer cells can be identified by their expression of CD24 and EpCAM.

"The theme for both systems is that we are measuring exosomes in blood for doing cancer diagnostics and monitoring treatment," Lee said.

Exosomes are valuable for diagnostics because they could be applied to identify virtually all types of cancers that have associated biomarkers, he added.

Using both the POC and high-volume tests, the group has looked into doing diagnostics for many types of cancers, including brain, colorectal, ovarian, pancreatic, and others. Outside of using the technology for cancers, it is investigating the use of exosome-based biomarkers in testing for Alzheimer's and kidney diseases. Lee noted that the team is using urine samples for kidney disease testing, because of urine’s proximity to the site of the condition. 

Although the group’s two exosome-based diagnostic tests would cater to different diagnostic needs, Lee said he sees a clear connection between them. "The high-throughput system is useful for biomarker discovery and validation where you need large volumes of test data," he said. "Once, you've validated the biomarkers, you could transfer that information to small clinics or doctor's offices, and you could then do exosome screening.

"We envision that the same type of tests that are now done in a doctor's office or small clinic can be done using exosomes and an affordable point-of-care device," Lee said, adding that the iMEX POC test can be built for around $100 in equipment costs.

"The information you get from blood could be used for cancer diagnostics, of course, but in the clinic or hospital setting, we are also interested in figuring out whether patients are responding to treatment, and if they are not responding, we can change the treatment strategy," Lee said.

Many research groups are investigating the biological functions of exosomes, but the effort to develop diagnostic tests is quite recent, Yoon-Kyoung Cho, a professor of biomedical engineering at Ulsan National Institute of Science & Technology, South Korea, said recently in an interview.

Researchers are searching for suitable and affordable ways to isolate exosomes so that they can be measured and used for clinical diagnostics. For example, Cho is developing a liquid biopsy-based lab-on-a-disc that incorporates centrifugal force and nanoporous membranes to isolate exosomes.

Cho said she believes that Lee's group at Harvard is doing "pioneering" work among initiatives to develop diagnostic tests that measure exosomes. 

Much work has been focused on isolating the full spectrum of exosomes circulating in a blood sample, and then searching their RNA or DNA en masse for cancer biomarkers.

In addition to the methods employed by the nPLEX and iMEX platforms, other approaches have emerged that could lead to clinical use. One such approach is to use surface markers to detect exosomes specific to a particular type of cancer and isolate them from the background of other circulating vesicles, cells, and cell-free nucleic acids.

Peregrine Pharmaceuticals recently reported on its own efforts in this area after licensing IP from the University of Texas Southwestern last year for the detection of exosomes that express the protein phosphatidylserine.

The UT Southwestern investigators who developed the approach reported that they were in fact able to distinguish between healthy subjects and patients with ovarian tumors based on the levels of PS-positive exosomes in their plasma.