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Map Diagnostics Developing Mass Spec Test for Down Syndrome

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NEW YORK (GenomeWeb) – Looking to move into a booming segment of the molecular diagnostics market, UK-based Map Diagnostics is developing a mass spectrometry-based test for detecting Down syndrome as early as eight weeks into a pregnancy. 

With a planned launch at the end of 2016 or in early 2017, the proteomics test would use a small sample of urine to generate results in less than one day, company officials said. 

Map Dx is still developing the test, which the company currently calls the Map Test, and is now in the midst of running a prospective study with urine samples to confirm initial results and to explore the use of the test on average-risk pregnancies. Company officials told GenomeWeb that the proteomic test could generate results with a 10 ml sample of urine. 

Preliminary results for the test were published in March in Clinical Proteomics. In the study, Map Dx said that researchers were able to distinguish Down syndrome in urine samples with 70 percent sensitivity and 100 percent specificity at 15 to 17 weeks into the pregnancy. But company officials told GenomeWeb said that the test is able to achieve sensitivity of about 90 percent with specificity between 5 percent and 20 percent, depending on the cutoff. 

Map Dx has three overriding principles in developing the test — to make it inexpensive, easy to use, and fast in getting sample to results. "You want something that's going to give you diagnostic accuracy," Map Dx CSO Stephen Butler told GenomeWeb, "but the biggest thing is you want something that's simple, straightforward, and above all … cheap." 

The Map Test, he added, will be developed as a "very high-quality screening test for a very, very affordable price with the idea that everyone can be offered the test. … Within minutes after doing a spectral analysis and applying some diagnostic algorithms on the spectra that's generated, you've got what you want out of a screening technology." 

Traditionally, testing for Down syndrome has employed immunoassays, sometimes augmented by ultrasound. Most recently, non-invasive prenatal tests — such as Sequenom's MaterniT21 Plus, Roche business Ariosa Diagnostics's Harmony, Illumina business Verinata Health's Verifi, and Natera's Panorama — have entered the fray. Such tests also detect for other aneuploidies, including trisomy 18, or Edwards syndrome, and trisomy 13, or Patau syndrome, and are rapidly gaining traction in the prenatal testing space. 

Map Dx officials, however, questioned the use of NIPT as a screening tool for a wide population. While some studies have suggested that some of the tests may have utility for average-risk pregnancies, in general, they are used for high-risk populations. Also, Map Dx officials said, the cost of an NIPT preempts them from being used as a general screen. For example, Quest Diagnostics recently launched an in-house developed NIPT prenatal screening test for fetal chromosomal abnormalities in high-risk pregnancies called QNatal Advanced priced at $2,800.

In contrast, Butler said that upon launch Map Dx's test will be priced in the hundreds of dollars, making it more widely affordable. He further noted that results from the Map Test can be generated in less than one day — in some instances, less than one hour — compared to between three days to about a week with NIPT. 

However, with NIPT gaining broad adoption and some acceptance as a testing technology for average-risk pregnancies, Map Dx could face a formidable challenge in trying to break into the aneuploidy testing space. Butler said that it's still too early to say how Map Dx would compete against the NIPT firms. "We're not particularly wedded to any route to market," he said. 

Mass spec equals mass adoption? 

Map Dx is using MALDI-TOF mass spec technology for its test, partly because of its previous experience with the technology in other work and partly because the technology lends itself to the company's goal of developing a Down syndrome test as a screening tool, company officials said.  

The technology is increasingly being used in clinical microbiology applications, and the same capabilities that make MALDI-TOF useful for identifying and typing microorganisms make it an appropriate platform for developing a screening test for Down syndrome, Map Dx executives told GenomeWeb. 

According to Butler, the technology can be a quick and cost-effective method for high-volume testing for certain conditions, such as Down syndrome, for which all expectant mothers in the UK are screened. MALDI-TOF is designed specifically for protein profile analysis, and in comparison with other mass spec technology, it offers a robust, simple workflow. "You really can't do the type of large molecules that we're looking at on a triple-quadrupole" mass spec, for example, Butler said. 

A quadrupole instrument would likely require sample purification, and with a triple-quad, a researcher will likely find multiple charged ions. As a result, the spectra would need to be deconvoluted, Map Dx COO Ray Iles said, adding "it's going to be a mess. It will be really difficult to get the kind of spectra that we're looking at." 

Other mass spec platforms would also require running a sample through a high-performance liquid chromatograph, which would render any mass spec test "inviable as a diagnostic or a screening test," Butler said, as the upstream work would take too long and would not lend itself to a simple chemistry environment. 

In the Clinical Proteomics study, Map Dx analyzed 101 maternal urine samples at between 12 and 17 weeks into the pregnancies, and adopted a MALDI method that they previously used to identify glycosylation variation found in human chorionic gonadotrophin beta core fragment in order to analyze molecules in the high-resolution range of 3,000 to 5,000 mass-to-charge (m/z) ratio. 

Later, they raised the m/z range to between 6,000 and 15,000 m/z to circumvent the need for protein purification and found that urinary mass spectral profiles differed in the pattern of protein and glycopeptide molecules in the urine of women who carried a fetus with Down syndrome compared to women who carried a fetus without Down syndrome. 

Map Dx initially focused its test development efforts on hCG glycosylation and hCG glycol-variants and was able to see pattern shifts in the urine samples of pregnant women carrying a fetus with Down syndrome. However, the firm soon realized that other post-translational modifications could also have diagnostic purposes. 

"We broadened our view, and instead of focusing on individual molecules, we started looking at regions within entire profiles," Butler said. "And that's the basis of what we do now. We don't look for changes in molecules. We look at pattern shifts across ranges of molecules by analyzing certain regions within a mass spec." 

The company also noted the value of using urine for the Map Test. Other Down syndrome testing methods are generally blood-based (NIPT) or are invasive (amniocentesis). Urine, Map Dx officials said, is easily accessible, and unlike blood can be collected in settings where people don't have access to a healthcare system. Butler added that in some ethnic and religious cultures providing blood samples may be taboo. 

"Our initial stability studies indicate that there shouldn't be any problems with a few-days-old urine, no matter what happens to it," Butler said. 

Map Dx is now embarking on a prospective study in collaboration with Kypros Nicolaides, a professor of fetal medicine at King's College London. It also is exploring possible collaborations with other partners for the study with the goal of analyzing 10,000 urine samples. 

Having access to such a high number of samples would facilitate the company's efforts to develop the Map Test as a general screening tool. For the Clinical Proteomics study, the company was limited to high-risk pregnancies because it had trouble accessing urine samples from normal pregnancies, company officials said. In order to develop the test as an early screen for the general population, the company will need to have access to "true normals," or urine samples from normal pregnancies at a very early stage. 

Also, by looking at such a high number of pregnancies, the firm will have a clearer idea of the specificity for the test in a screening population. Once it can access more urine samples from normal pregnancies, COO Iles said that Map Dx anticipates it will be able to get the false-positive rate below 5 percent. 

Iles noted that in its study of a high-risk population, MAP found a certain amount of preeclampsia, "and we get unusual spectral patterns for preeclampsia. One of the things we're doing in our algorithms is saying, 'Can we differentiate preeclampsia as a separate grouping?'" 

"There are some interesting overlaps, and to differentiate these groups, we need high numbers," Iles said. 

When and if Map Dx launches its test, it will do so as a mass spec-based test, rather than as an immunoassay. The firm has used several different MALDI-TOF instruments and has not yet settled on any specific instrument to launch the test. The company anticipates it will launch it as a CE-marked test in Europe, while in the US, the preference is to make the test available as a laboratory-developed test. The plan is to make the test available through lab partners equipped with MALDI-TOF mass specs. 

Iles noted that although the test is currently targeted for Down syndrome, there is some consideration to expanding it to include other aneuploidies, including trisomy 18 and 13. "It's a matter of getting the samples and looking to see what kind of profiles they give us," Iles said. 

Butler said that preliminary results have indicated that the MAP Test may be able to detect T18 and 13, "but we haven't built any algorithms around that yet." 

Also in Map Dx's pipeline are tests for non-pregnancy-related conditions, including cancer, and an announcement could be made soon about a blood-based test for sickle-cell anemia that MAP is developing based on a pin prick of blood, company officials said.

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