ARCEDI Biotech Readying Cell-Based NIPT for Commercialization as Clinical Studies Continue (GenomeWeb)

NEW YORK (GenomeWeb) – Arcedi Biotech of Denmark has been collaborating with six Danish hospitals to clinically validate its technology for isolating circulating fetal cells from maternal blood and analyzing their DNA for noninvasive prenatal diagnostics.

Arcedi hopes to commercialize the technology in the near future through a large diagnostic player,  said CEO Palle Schelde, ideally by becoming part of such a company. It has not licensed the technology yet but is in “preparation of a structured sales process,” he added.

“To unleash the huge commercial potential of this technology into the prenatal market, we have now reached a point in the company’s history where this technology is ready for commercialization,” Schelde said.

Last month, Arcedi researchers and their collaborators at Aarhus University Hospital published five clinical cases that are part of the larger validation study in Prenatal Diagnosis, showing that cell-based noninvasive prenatal testing can detect chromosomal aneuploidy and subchromosomal aberrations, and comparing the results to those of invasive testing.

However, challenges remain to automate the technology for higher throughput and to reduce its cost, which the researchers say is currently similar to that of invasive testing.

In addition, clinical trials to determine the test’s sensitivity, specificity, and positive predictive value still need to be conducted. Finally, cell-based NIPT will likely grapple with some of the same issues as other prenatal tests, for example the detection of mosaicism.

Cell-based NIPT from maternal blood has been pursued for decades, and a number of academic and commercial groups have recently made progressand are working towards clinical tests. Unlike cell-free NIPT, which analyzes a mix of fragmented DNA from the mother and fetus and has taken off in recent years, cell-based NIPT targets pure fetal DNA for analysis. As such, it promises to be able to offer the same high-quality results as invasive methods, such as amniocentesis and chorionic villus sampling, including chromosomal aberrations and copy number variants. As a diagnostic test, it would not require confirmation by invasive testing, which is currently recommended for positive cell-free NIPT results.

But circulating fetal cells  are rare in maternal blood, and it has been difficult to isolate them consistently and in large enough quantities from each and every sample, a challenge that Arcedi says it has now overcome.

Arcedi’s method, which was described a year ago in a publication with collaborators at Baylor College of Medicine, uses several antibodies against markers to enrich and stain trophoblasts from maternal blood. The company holds intellectual property to those markers that is valid until 2031, according to Chief Technology Officer Ripudaman Singh. In addition, it uses a proprietary method for processing the blood, he said, and has developed an algorithm for identifying fetal cells under a fluorescence scanner. Fetal cells are individually picked, followed by whole-genome amplification of pooled DNA from several cells, which can then be analyzed by either array comparative genomic hybridization (aCGH) or next-generation sequencing.

According to Ida Vogel, a clinical geneticist at Aarhus University Hospital and the senior author of the recent study, the five cases presented in the paper are part of an ongoing validation study for which Arcedi has analyzed about 600 samples so far. The company has been able to isolate fetal cells from every sample, she said, including from obese women, where cell-free NIPT sometimes cannot obtain sufficient fetal DNA.

Clinicians in Denmark have generally been skeptical of cell-free NIPT, Vogel said, because it only looks for Down syndrome and a few other conditions, when fetal malformations can be caused by many types of chromosomal aberrations. As such, her hospital was interested in collaborating with Arcedi, because it allowed them to study a test that requires only a blood sample but looks for more than just Down syndrome.

In her region of Denmark, she said, first-trimester screening, which is still the standard, identifies about 5 percent of women as high risk, of whom 80 percent currently opt for invasive testing and 20 percent for cell-free NIPT.

For their study, the Aarhus researchers collected 30 milliliters of blood from women who had been determined to be at high risk following first-trimester screening and had opted for invasive testing by CVS. The blood was sent to Arcedi for fetal cell isolation and DNA amplification. For this study, Arcedi used a capillary-based CellCelector from Automated Lab Solutions to pick the fetal cells and the Picoplex WGA kit from Rubicon Genomics to perform WGA. According to Singh, the process takes about 14 hours from blood collection to DNA amplification, and aCGH adds another couple of days to the test.

On average, the researchers isolated 13 fetal cells per blood sample and analyzed DNA from pools of two to seven cells.

The Aarhus researchers then performed aCGH on both the amplified fetal cell DNA and the invasive CVS samples, using arrays from Agilent Technologies. For two of the five cases, they also performed cell-free NIPT, using Illumina’s platform and VersiSeq NIPT analysis software.

Cell-based NIPT was able to replicate results from invasive testing in all five cases, including trisomy 21, trisomy 13, trisomy 2, partial trisomy 21 involving a 12.4-megabase duplication, and an unbalanced translocation between chromosomes 4 and 8. In the two cases where it was used, cell-free NIPT also detected abnormalities

However, for the trisomy 13 and trisomy 2 cases, invasive testing also identified high-grade mosaicism, which cell-based NIPT was unable to pick up because it analyzed so few cells.

In addition, cell-based NIPT delivered one false-positive result, a duplication in chromosome 19 that CVS testing did not come up with, which likely resulted from DNA quality issues. Vogel said that chromosomal microarrays were initially plagued by similar quality problems, but that those were solved over time and will likely be solved for cell-based NIPT in the future, too.

Overall, she said, it is encouraging that cell-based NIPT can identify not only chromosomal aneuploidies but also smaller aberrations, such as deletions and duplications. However, there were some — not shown in the publication — that were too small to be picked up by the test. The current detection limit is somewhere between 5 and 10 megabases, she said, but there is potential to improve the resolution of the test.

Vogel said her hospital is about to embark on another, year-long study with Arcedi, scheduled to start in January, in which the partners hope to provide cell-based NIPT as an additional test to at least 200 women who opt for cell-free NIPT.

Besides proving the test’s sensitivity and specificity, Arcedi would need to reduce its cost for routine clinical use, Vogel said. At the moment, costs are on the order of $2,000, a similar price range as invasive testing.

Singh said that Arcedi has so far focused on obtaining fetal cells from every sample and that the current technology has not been automated or optimized for cost. “Now that we have achieved our goal of isolating fetal cells from every sample, this is where we are currently focusing,” he said.

According to Vogel, one of the main advantages of the test is its potential to find more types of disorders than cell-free NIPT, including those passed on to the fetus from the mother. “I don’t think it will ever get to a quality compared to invasive testing,” she said. “But the advantage is, of course, that you don’t have to take an invasive sample.”

“If the price becomes reasonable, it could be a screening test for all pregnant women,” said Niels Uldbjerg, a professor of obstetrics and gynecology at Aarhus University Hospital, another study author. “That would be the ultimate use.”

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