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Following Improvements in Noninvasive Fetal Cell Isolation, First Prenatal Tests Expected in 2016

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NEW YORK (GenomeWeb) – Noninvasive prenatal testing of cell-free fetal DNA from maternal blood has taken off in recent years, but some researchers say assaying noninvasively obtained fetal cells remains the "holy grail" because such tests could offer a much more detailed view of the fetal genome, unadulterated by genetic material from the mother, while avoiding the risk of invasive procedures.

At the Advances in Prenatal Molecular Diagnostics annual meeting in Boston last week, several academic and commercial research groups presented their work on isolating and analyzing fetal cells from maternal blood or from cervical samples, and some said they plan to launch prenatal genetic tests as early as 2016.

It has been known for several decades that fetal cells can make their way into the mother's blood or into the cervix during pregnancy, but so far, researchers have had trouble separating, identifying, and isolating these cells.

One problem is that the cells are exceedingly rare: according to some estimates, only one in a billion cells in maternal blood are of fetal origin. Another challenge is that fetal cells come in different types and it has been tricky to find specific markers for them.

Most researchers have focused their efforts on three types of fetal cells: trophoblasts, which are derived from the placenta; fetal nucleated red blood cells; and fetal leukocytes.

At last week's meeting, researchers from Baylor College of Medicine; Arcedi Biotech; the University of California, Los Angeles; the University of Paris Descartes; Wayne State University; Columbia University in collaboration with KellBenX; Ascendas Genomics; and Silicon Biosystems reported on a variety of techniques to enrich and identify fetal cells prior to genomic analysis.

Baylor College of Medicine has been working towards a genomic test on fetal cells isolated from maternal blood, collaborating with two companies, RareCyte of Seattle and Arcedi Biotech of Denmark, on fetal cell isolation.

Arcedi has discovered highly specific ectodermal and mesodermal markers for fetal endovascular trophoblasts, and has been able to use these to enrich and identify fetal cells from blood samples collected from pregnant women in their first trimester.

RareCyte, for its part, has developed the AccuCyte system that separates different blood cell types according to their density, and the CyteFinder instrument with the CytePicker module to select and retrieve labeled single cells under a microscope for genomic analysis. The company focuses on circulating tumor cells, prenatal testing, and infectious disease as potential applications.

According to Arthur Beaudet, chair of the department of molecular and human genetics at Baylor and Chief Medical Officer of Baylor Miraca Genetic Laboratories, using these technologies, followed by whole genome amplification, his team has been able to isolate single fetal cells, identify them based on short tandem repeat (STR) analysis, and detect chromosomal aneuploidies using arrayCGH. One of the challenges, he said, has been that some fetal cells appear to be in the S-phase of the cell cycle, which can interfere with the results, but several fetal cells could be pooled.

His team is now planning to conduct a validation study on women undergoing invasive diagnostic testing for chromosomal aneuploidies, in which they will compare arrayCGH results from invasively and noninvasively obtained fetal cells. The goal, he said, is to launch a clinical prenatal test — the resolution of which has yet to be determined — at Baylor Miraca within the first half of 2016.

Hsian-Rong Tseng, a professor at the California NanoSystems Institute at UCLA, talked about developing an "espresso machine" for isolating rare cells, such as circulating tumor cells or fetal cells, from blood using so-called NanoVelcro microchip technology. Two sister companies  — CytoLumina Technologies and FetoLumina — are developing the approach, which is protected by eight patent applications, for applications in cancer diagnostics and in prenatal testing, respectively, he said. This summer, Sorrento Therapeutics exclusively licensed the NanoVelcro Circulating Tumor Cell profiling assay from the firms for certain applications.

In addition, Tseng's group is collaborating with PacGenomics, a company based in Agoura Hills, California that focuses on single-cell genomics for preimplantation genetic screening, prenatal testing, and cancer screening, as well as with BGI in Shenzhen for next-gen sequencing and with a hospital in Taiwan.

The most recent iteration of the NanoVelcro technology relies on a thermo-responsive chip with a "hairy surface" of polymer brushes that is coated with capture antibodies for a specific cell type. When the temperature drops, the polymers "stand up", so the antibodies are no longer exposed and the cells are released. Two rounds of purification result in very pure cells, he said.

In 2016, the NanoVelcro technology may become available for routine clinical use, Tseng said. In proof-of-concept studies, the researchers have shown that they can detect trisomies in fetal cells using arrayCGH. The purity of the cells is currently under 35 percent, but they are planning to improve it to 70 to 90 percent by 2017 or 2018, he said, and to bring costs down to under $10 per sample.

Patrizia Paterlini-Brechot, a professor of cellular and molecular biology at the University of Paris Descartes and a founder of Rarecells, presented results from another technology for isolating rare cells, called ISET for Isolation by Size of Epithelial Tumor/Trophoblastic cells. The patented approach, which was commercialized by Rarecells, uses filters with certain pore sizes to enrich circulating trophoblastic cells from blood, followed by staining, laser microdissection of individual cells, whole-genome amplification, and single-cell genomic analysis.

In a paper that has just been accepted for publication, the researchers showed that the method can also be used to isolate trophoblasts from cervical samples collected from the external part of the cervix. They found that the concentration of trophoblasts in cervical samples is higher than in blood.

Paterlini-Brechot and her colleagues, in collaboration with Rarecells, are currently testing ISET for trisomy 21 detection in a clinical trial that aims to enroll 500 women and has analyzed 147 so far, but no results are available yet.

In addition, they are exploring a combination of the Rarecells ISET filtration technology with the CellCelector technology from ALS Automated LabSolutions, which allows for the automated transfer of single cells. The group has also been testing different whole-genome amplification methods on single fetal cells.

A group led by Randall Armant, a professor of obstetrics and gynecology at Wayne State University School of Medicine, is also isolating trophoblasts from cervical samples, using an approach called TRIC, for Trophoblast Retrieval and Isolation from the Cervix, that the researchers published in 2014 and that involves the use of magnetic particles covered with anti-HLA-G to capture the trophoblasts. The method has potential for prenatal genetic testing, he said, as well as for assessing the health of the placenta in ongoing pregnancies.

Three other companies — KellbenX, Ascendas Genomics, and Silicon Biosystems — have been exploring methods for isolating fetal cells from maternal blood, which were presented at last week's meeting.

Brynn Levy, a professor of pathology and cell biology at Columbia University Medical Center, has been collaborating with KellBenX, which is based in Great River, New York, on isolating fetal nucleated red blood cells, using monoclonal antibodies to the 4B9 cell surface marker. The partners are conducting a blinded validation study to analyze fetal cells for trisomies and microdeletions or microduplications.

Ascendas Genomics, which was co-founded a year ago by molecular diagnostics firm DaAn Gene of Sun Yat-sen University and is located near Hong Kong, selectively lyses red blood cells while protecting fetal cells, using a proprietary stabilizer. It then further enriches the fetal cells using an anti-CD-71 antibody, followed by fetal-cell identification, single-cell retrieval, whole-genome amplification, and genetic analysis.

Silicon Biosystems has already commercialized its DEPArray technology, which uses dielectrophoresis to trap individual cells in "cages" and move them around on a chip. Its DEPArray system combines this technology with imagine-based cell selection to recover intact individual cells of interest — such as circulating tumor cells or fetal cells — for analysis. For prenatal testing, these include aneuploidy detection, SNP and copy number variation analysis, and STR profiling.

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