Noninvasive Prenatal Diagnostics: How Much Closer to Reality?

Article preview reprinted from IN VIVO -  October/November, 2009  

Whether the astonishing missteps by Sequenom, which earlier this year disclosed it could not support its data for a non-invasive Down Syndrome test, were merely poor management or a reality check for the field of non-invasive prenatal disgnostics, the NIPD opportunity is compelling. But the profession also understandably balks at obtaining information that is not then clinically actionable -- an issue that could further amplify in importance as technologies like microarrays and direct DNA sequencing increase become more prevalent. Read more...

Noninvasive Prenatal Diagnostics: How Much Closer to Reality? 

Article preview reprinted from IN VIVO -  October/November, 2009  

The Sequenom affair may have dented expectations and stained credibility in the emerging field of noninvasive prenatal diagnostics, but the real question is whether any technology works yet.

The complicated matrix of screening followed by diagnosis suggests that in the end, the opportunities in the prenatal space will yield various combinations of solutions.
But the profession understandably balks at obtaining information that is not then clinically actionable. That issue could further amplify in importance as the use of technologies like microarrays and direct DNA sequencing increases.
Strategies around isolating whole fetal cells from maternal blood have given way to the capture of free circulating fetal nucleic acids.
That the same technologies are used to identify circulating tumor cells makes it likely that the pursuit of cancer diagnostics will be a main driver for fetal cell extraction.

It remains to be seen whether the astonishing missteps by Sequenom Inc., which earlier this year disclosed that it could not support the clinical results it had claimed for a noninvasive test for Down syndrome (trisomy 21), were merely a circumstance of poor company management--and therefore dismissible as an anomaly--or a statement that a reality check for the field of noninvasive prenatal diagnostics (NIPD) is in order and that expectations should be ratcheted way back.

It's conceivable that Sequenom's test could be revalidated and even launched in early 2010, and credibility restored. Conversely, the data may ultimately prove to be so weak that the company, which analysts at one time were saying could sport a market cap in excess of $2.5 billion and some hedge fund managers had bet would go even higher (it's currently under $200 million), is sold for scrap IP. Whichever way that situation shakes out, however, the NIPD opportunity is compelling: replace the current invasive testing for genetic disorders, which entails either chorionic villus sampling (CVS) or amniocentesis, with noninvasive tests using a blood draw; extract circulating cell-free nucleic acids or even whole fetal cells; interrogate the nucleic acids to detect changes in chromosome number or gene copy number variation; and, ultimately, leverage the technology to expand the panel for tests beyond Down syndrome, the other trisomies (extra copies of chromosomes 13 or 18), and chromosomes X and Y to also include microdelection and microduplication syndromes that are too small to be detected by current cytogenetic chromosome analysis (karyotyping).

"The opportunity for noninvasive prenatal diagnostics is something that has to happen," says Lissa Goldenstein, former CEO of Artemis Health Inc. "There's got to be a better way."

Driving the argument are advances in methodologies for identifying and isolating fetal nucleic acids circulating in the mother's blood (cell-free DNA or RNA) and in the tools for analyzing that cell-free material for genetic mutations, including kits for isolating free nucleic acids from plasma, amplification technologies such as digital and single-cell PCR, microarrays, mass spectrometry, even direct DNA sequencing, which many argue will become routine as costs come down toward the $1,000 genome goal. (In the past four years alone, sequencing costs have decreased by a factor of 10,000.)

The use of many of these techniques was at the heart of Sequenom's development of its SEQureDx trisomy 21 test, and the claims it had been making for its sensitivity and specificity--at least until April 2009, when the company acknowledged serious data tampering and announced that it therefore had to revalidate all of its clinical data in new studies, ultimately leading to the dismissal of the management team in September.

Sequenom has been focused on Down syndrome using methods for detecting cell-free RNA and also DNA, based on work done by long-time collaborator Dennis Lo, MD, PhD, of the Chinese University of Hong Kong. Those efforts mirror the discoveries made by sequencing pioneer Stephen Quake, PhD, of Stanford University, the co-founder of Fluidigm Corp., a microfluidics specialist, and next-generation sequencer Helicos BioSciences Corp. Quake published his work in the Proceedings of the National Academy of Sciences (PNAS) in October 2008, two months before similar work by Lo appeared, also in PNAS. Stanford has licensed Quake's inventions for detecting fetal genetic characteristics in maternal plasma, including the use of a combination of digital PCR and high-throughput shotgun sequencing, to both Fluidigm, which sells PCR kits, and Artemis Health (formerly Living Microsystems Inc.), one of the handful of young companies that, like Sequenom, is developing NIPD content.  

- Mark L. Ratner

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Companies mentioned in this article:

Artemis Health Inc.

Chinese University of Hong Kong

Columbia University

Fluidigm Corp.

Harvard University

Harvard Medical School

Helicos BioSciences Corp.

Ikonisys Inc.

Lenetix Medical Screening Laboratory Inc.

Luminetx Corp.

Luminex Corp.

National Institutes of Health

Parsortix Inc.

PerkinElmer Inc.

NTD Laboratories Inc.

Spectral Genomics Inc.

Sequenom Inc.

Stanford University

Tufts University

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