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Angle to Enter NIPT Market With Rare Cell Isolation Platform

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NEW YORK (GenomeWeb) – UK-based Angle aims to enter the noninvasive prenatal testing (NIPT) market with its Parsortix cell-based enrichment system. The company recently released results from a pilot study demonstrating the enrichment of circulating fetal cells.

Researchers in the prenatal testing space have been attempting to extract fetal cells from a pregnant woman's bloodstream for decades, with mixed results, and all current providers of NIPT rely on cell-free DNA rather than fetal cells.

Peggy Robinson, VP of Angle, explained that an undisclosed client had asked Angle to see if it could apply the Parsortix system — currently used for enriching tumor cells in the oncology space — to rare fetal cells for prenatal diagnosis of birth defects. The firm's researchers therefore evaluated Parsortix to isolate circulating fetal cells from the maternal bloodstream.

In the unpublished study, Angle’s researchers collected 7 milliliters of whole blood samples from 21 pregnant women, in addition to 20 age-matched female controls. The team collected samples from two patients during their first trimester, 10 during their second trimester, and nine during their third trimester of pregnancy.

From the blood samples, the system separated and enriched rare cells based on cell size and compressibility via a disposable microscope slide-sized cassette.

According to Robinson, each cassette contains a ribbon with a series of stair steps. At the top of the steps is a gap that cells move through as they traverse through the microfluidic system. Smaller cells, including red and white blood cells, fly through the gap, while the larger, rare cells are wedged on the steps and cannot move through the gap.

"Once you capture the targeted cells, you can [either] stain them if you want to, or turn a valve first to reverse the flow, and then harvest the cells," Robinson explained. "You then collect the cells in a buffer solution, leading to an enriched cell population."

In the study, the team analyzed the samples with both FISH and cytological staining. Using Abbot's AneuVysion multicolor DNA probe Kit, the team tracked X and Y chromosomes, as well as trisomies 13, 18, and 21.

The researchers found that the Parsortix system successfully enriched fetal cells from maternal blood samples. They observed large putative fetal cells — showing small nuclei and large, distorted cytoplasm — on cytospun slides from women during all three trimesters of pregnancy.

Out of the 19 samples from pregnant women analyzed by FISH, the team found eight that had at least one fetal cell containing one X signal and one Y signal, meaning it was of male origin .

In addition, the team processed one blood sample from a pregnant woman diagnosed with a Down syndrome fetus, identifying fetal cells with three chromosomes 21.

Based on the pilot study, Angle believes Parsortix could be used to isolate, enrich, and characterize rare fetal cells from maternal blood to diagnose conditions such as Down syndrome and fragile X syndrome prenatally. However, the researchers noted that they will need to pursue further studies to develop an effective NIPT assay.

"The fact you can get access to these cells, which are viable, living cells, is important," Robinson said. "For a molecular analysis, whether you decide to do [next-generation sequencing] or pick cells and perform other types of assays, it's from a tube of blood and easier" than invasive assays.

Instead of developing a fully commercialized workflow for NIPT applications of the Parsortix system on its own, Angle is looking to partner with someone. Robinson declined to comment on the eventual cost of an assay for the NIPT space at this time. 

"Since you have access to the cells, there are a bunch of things you could do," Robinson said. "There are commercial entities that are more experienced or well-connected, and giving them access to the enriched cell population would make their work easier."

As Angle continues to develop an assay for the NIPT market, it will be entering a crowded field of competitors attempting to develop methods for extracting fetal cells noninvasively from blood samples and analyzing them for genetic defects.

Danish firm Arcedi Biotech, for example, published a validation study on its technology for isolating circulating fetal cells from maternal blood a year ago. Also, a team led by Hsian-Rong Tseng, a professor of molecular and medical pharmacology at the University of California, Los Angeles, is developing an assay based on "NanoVelcro" microchips and laser capture microdissection to isolate fetal cells from the mother's blood or cervix. UCLA has licensed the technology for fetal cell isolation to FetoLumina Technologies, a startup Tseng founded.    

In addition, researchers at Wayne State University School of Medicine have developed a tool using magnetic nanoparticles to retrieve trophoblasts from Pap smears and profiled their DNA via next-generation sequencing for short tandem repeats and SNVs. PerkinElmer has licensed that technology and the researchers founded a startup called Advanced Reproductive Testing to develop a commercial version of the assay. 

Robinson argued that Parsortix stands out from other fetal cell isolation technologies because of its ability to “reliably capture fetal cells from pregnant women’s blood and to easily and efficiently harvest the cells for analysis.” In addition, she noted that Parsortix does not use any chemical interaction with the cells -- as in antibody-based approaches – and leaves the cells in “pristine condition” for downstream analysis.

Art Beaudet, a molecular and human genetics professor at Baylor College of Medicine, argued that Angle will need to "absolutely prove" that the cells it traces are fetal in nature. In addition, he said that researchers will need to know how many fetal cells can be recovered in what proportion of pregnancies, and in what periods of gestation.  Beaudet's team previously partnered with RareCyte and Arcedi in a 2016 study demonstrating that they could collect fetal trophoblasts from maternal blood as early as 10 weeks of gestation.

Tseng also argued that Angle will need to test Parsortix on a much larger cohort, as previous studies have examined more than 2,000 maternal blood samples.

Regarding the small sample size, Robinson noted that “this was a small feasibility study, and this [population size] was the distribution of patients we were able to access at the time.”

"The problem for this type of approach (fetal-cell isolation + FISH) is that a practical NIPT solution cannot use Y chromosome and/or trisomy as fetal cell markers," Tseng explained. "The new consensus in the field for fetal cell-based NIPT" is that the technology "will have two capacities [including] whole fetal genomic profiling (by microArray or NGS) and forensic evidence (short tandem repeat fingerprints) to confirm [a] fetal-maternal relationship."

According to Tseng, Angle's technology will need to include both methods to "claim visibility in the field." In general, he emphasized that NIPT researchers have struggled to develop an accurate and precise method of fetal cell extraction because a very small number of fetal cells circulate in the maternal bloodstream. Beaudet added that there is about one fetal cell per milliliter of mother's blood, while there are billions of cells from the mother.

"Even if cells could have been obtained 10 years ago, there would not have been technology, especially NGS, to do a great analysis," Beaudet said, adding that Angle needs rigorous documentation of what percent of pregnancies it can study successfully, to define what represents an adequate result and the level of resolution for detections of deletions, and to show reliable detection of point mutations, such as for cystic fibrosis.

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