Cell Based NIPT using ARCEDI technology

ARCEDI Biotech has developed a high-throughput, scalable and proprietary technology for isolating rare circulating fetal cells from maternal blood, with applications in Non-invasive Prenatal Testing (NIPT), both after normal and assisted (preimplantation genetic testing) conception, pre-term birth, and hydatidiform mole diagnosis.

With its well-established flagship technology ARCEDI Biotech ApS aims at achieving the goal of NIPT based on fetal cells enriched from pregnant women’s blood, in an automated and non-subjective manner.

The perspective for ARCEDI technology is to develop a no risk method of providing pregnant women with accurate information about the genetic status of their unborn child. The solution, based on simple blood sampling, provided by ARCEDI holds the potential to replace the current invasive procedures, known to induce unintended abortions, and unnecessary stress.

The potential use of fetal cells in NIPT is well acknowledged. However, because of the rarity of these cells in maternal circulation, limited knowledge of the cell type, and the absence of specific markers to enrich the fetal cells, has hindered the development of cell-based NIPT.

BOTTOM-UP SCIENCE

For the last 13 years ARCEDI Biotech addressed these issues. The scientific team at ARCEDI was the first to describe that extravillous trophoblasts are the fetal cell type that circulate in maternal blood (1), and also used markers against these cells to successfully enrich them from the blood (2). In a 2016publication in ‘Prenatal Diagnosis’, scientists at ARCEDI, among others, described an improved method of enriching fetal cells and also used 1-2 fetal cells to perform chromosomal and subchromosomal testing without invasive sampling (3). This was one of the first studies to report successful genetic analyses on fetal cells enriched from maternal blood.

In a 2017 joint publication by ARCEDI and Aarhus University Hospital entitled “On the road to replacing invasive testing with cellbased NIPT: Five clinical cases with aneuploidies, microduplication, unbalanced structural rearrangement, or mosaicism”, cases with smaller copy number variations in the fetal genome detected on circulating fetal cells isolated from maternal blood were presented (4). In a recently submitted manuscript, more cases have been presented where rare fetal conditions are detected by cbNIPT, but not by cfNIPT (5)

ARCEDI research has also focused on different factors and their possible impact on cbNIPT results. These include maternal BMI (6) postpartum circulation of fetal cells (7) and gestational age (8)

Recently, a manuscript in collaboration with six different regional hospitals in Denmark has been submitted for publication, where, following preimplantation genetic testing for monogenic disorders (PGT-M), the use of fetal cells for non-invasive prenatal diagnosis has been proposed as an alternative to invasive testing (9),

OTHER APPLICATIONS

Additionally, ARCEDI’s rare cell isolation and detection technology has been used for the isolation of other cell types with applications in preterm birth (10) and diagnosing hydatidiform mole (11).

PATENT PROTECTION

ARCEDI has three granted patents, and two submissions.

COMMERCIALISATION

As part of ARCEDI’s cell-based non-invasive test offering in Denmark, pregnant women who are stratified as ‘high risk’, based on ultrasound scan, maternal age, and maternal serum screen, have a choice of either opting for invasive CVS, or cell-free NIPT. Those women who opt for cell-free NIPT are additionally offered cell-based NIPT.

Together with various stakeholders in the field of preimplantation genetic diagnosis, ARCEDI is exploring the possibility of offering its cell-based NIPT as an alternative to CVS for screening the fetus in the first trimester.

REFERENCES

  1. Hatt L., Brinch M., Singh R., Møller K., Lauridsen RH., Uldbjerg N., Huppertz B., Christensen B., Kølvraa S. (2014). Characterization of Fetal Cells from the Maternal Circulation by Microarray Gene Expression Analysis – Could the Extravillous Trophoblasts Be a Target for Future Cell-Based Non-Invasive Prenatal Diagnosis?Fetal Diagnosis and Therapy. 35: 218-227.
  2. Hatt L., Brinch M., Singh R., Møller K., Lauridsen RH., Schlutter JM., Uldbjerg N., Christensen B., Kølvraa S. (2014). A new marker set that identifies fetal cells in maternal circulation with high specificityPrenatal Diagnosis. 34 (11): 1066-1072.
  3. Kølvraa S., Singh R., Normand E., Qdaisat S., Van den Veyver I.B., Jackson L., Hatt L., Schelde P., Uldbjerg N., Vestergaard E.M., Zhao L., Chen R., Shaw C., Bremen A., Beaudet A. (2016). Genome-wide copy number analysis on DNA from fetal cells isolated form the blood of pregnant womenPrenatal Diagnosis. 36 (12): 1127 – 1134.
  4. Else Marie Vestergaard EM., Singh R., Schelde P., Hatt L., Ravn K., Christensen R., Lildballe DL., Petersen OB., Uldbjerg N., Vogel I. (2017). On the road to replacing invasive testing with cell-based NIPT: five clinical cases with aneuploidies, microduplication, unbalanced structural rearrangement or mosaicism. Prenatal Diagnosis. Nov;37(11):1120-1124.
  5. Hatt, Singh R., Christensen R., Ravn K., Christensen IB., Jeppesen LD., Nicolaisen BH., Kølvraa M., Schelde P., Andreassen L., Farlie R., Uldbjerg N., Vogel I. (2020). Cell-based non-invasive prenatal testing (cbNIPT) detects pathogenic copy number variations (Clinical Case Reports. Accepted for publication)
  6. Kruckow S., Schelde P., Hatt L., Ravn K., Petersen O.B.,Uldbjerg N., Vogel I., Singh R. (2018).  Does maternal body mass index affect the quality of circulating fetal cells available to use for cell-based noninvasive prenatal test in high-risk pregnancies? Fetal Diagnosis and Therapy. Sep 10:1-4.
  7. Anne van de Looij A., Singh R., Hatt L., Ravn K., Jeppesen LD., Nicolaisen BH., Kølvraa M., Vogel I., Schelde P., Uldbjerg N. (2020). Do Fetal Extravillous Trophoblasts Circulate in Maternal Blood Postpartum? 99(6):751-756.
  8. Ravn R, Singh R. Hatt L., Kølvraa M., Schelde P., Vogel I., Uldbjerg N., Hindkjær J. (2020).The number of circulating fetal extravillous trophoblasts varies from gestational week 7 to 19.  (Reproductive Sciences. Online Ahead of Print).
  9. Christian Liebst Frisk Toft, Ingerslev HJ., Kesmodel US., Hatt L., Singh R., Ravn K., Nicolaisen BH., Christensen IB., Kølvraa M., Jeppesen LD., Schelde P., Vogel D., Uldbjerg N., Farlie R., Sommer S., Østergård MLV., Jensen AN., Mogensen H., Kjartansdóttir KR., Degn B., Henrik Okkels H. Ernst A., Pedersen IS. (2020). Cell-based non-invasive prenatal testing for monogenic disorders: Confirmation of unaffected fetuses following preimplantation genetic testing. (Manuscript Submitted)
  10. Lamont RF., Richardson LS., Boniface JJ., Cobo T., Exner MM., Christensen IB., Forslund SK., Gaba A., Helmer H., Jørgensen JS., Khan RN., McElrath TF., Petro K., Rasmussen M., Singh R., Tribe RM., Vink JS., Vinter CA., Zhong N., Menon R. (2020). Commentary on a Combined Approach to the Problem of Developing Biomarkers for the Prediction of Spontaneous Preterm Labor that Leads to Preterm Birth. (Placenta. Online Ahead of Print).
  11. Sunde L.,Singh, Ravn K., Schelde P., Hansen ES., Uldbjerg N., Niemann I., Hatt L. (2020). Hydatidiform mole diagnostics using circulating gestational trophoblasts 1 isolated from maternal blood. (Manuscript Submitted).