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Greenwood Genetic Center Nets $275K to Develop Array-Based Autism Test

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The National Institutes of Health has awarded Greenwood Genetic Center $275,000 to support the development of a test for autism spectrum disorders. GGC will use Biolog's Phenotype Microarray platform in the planned two-year study.

Charles Schwartz, director of research at Greenwood, SC-based GGC, is the principal investigator on the project. He told BioArray News this week that the work builds upon previous studies conducted using Biolog's arrays that showed that a reduction of nicotinamide adenine dinucleotide production in the presence of tryptophan in lymphoblastoid cells can be used to diagnose patients with ASD.

In those studies, Schwartz and colleagues observed that a reduction in NADH production was observed in 54 out of 56 patients with ASD, or 96.4 percent, when compared with controls. Using the fresh NIH funding, the GGC investigators now plan to validate those findings in a cohort of 50 additional patients and 50 additional controls employing customized Phenotype MicroArray plates.

Biolog's arrays are cell-based assays that can be used to determine up to 1,400 metabolic and chemical sensitivity phenotypes of mammalian cells. According to the firm, arrays are provided in 96-well plates pre-loaded with carbon-energy and nitrogen substrates, ions, hormones/cytokines and anti-cancer agents. Cells of interest are scanned for phenotypes by adding cell suspension to each well followed by the addition of Biolog's redox dye. In some wells, the cells are stimulated and in other wells inhibited. The generation of energy-rich NADH by the cells reduces the redox dye and brings about a color change.

Schwartz said that he initially adopted Biolog's arrays to profile males with X-linked intellectual disability syndromes, but as part of that study, his team analyzed 10 patients with ASD and noticed that as a group they had profiles quite distinct from all other patients they had analyzed. "Since this was so striking, we examined another 46 patients and made the same observation when compared to an equal number of controls," he said.

Now GGC will use custom designed Phenotype MicroArrays to validate those findings and hopefully produce a test that can be licensed to an interested partner for commercialization, Schwartz said. The new plates GGC will use will allow it to test 12 individuals per plate, using 160,000 cells per individual.

The proposed 100 samples to be screened, in addition to the 96 samples from the preliminary study, will give statistical power of 95.6 percent, Schwartz noted. Beyond that validation, though, GGC hopes to use the assay to evaluate the NADH production in the presence of tryptophan in fresh blood samples, according to Schwartz.

"Until now, our data has been generated using lymphoblastoid cell lines," he said. "Ideally, a test needs to use freshly isolated white cells," he added. "So we will now see if the findings can be replicated using these and, if so, [whether we] can make the diagnosis of ASD in a small, blinded study."

As a first step, the GGC team plans to use six patients and six controls that it has already tested to replicate the results observed in lymphoblastoid cell lines in fresh white cells, the team wrote in the grant's abstract. This first stage will allow the team to determine if it is able to observe the same low levels of NADH production in the presence of tryptophan in leukocytes as was observed in lymphoblasts.

After that, the GGC team will test fresh blood samples from 12 patients with ASD and 12 controls. Finally, it will test 24 patient and 24 control blood samples from new individuals in a blinded fashion to establish the predictive power of the test in patients with ASD.

"For this last part of the experiment, we will test each sample as soon as it arrives at our laboratory," the researchers said in the abstract. To do this, they will rely on a single row of eight wells on the customized plates for each individual, covering the rest of the plate with aluminum foil, to preserve the other rows for future tests.

If the team's preliminary findings in lymphoblasts are confirmed in leukocytes, then the GGC researchers believe that they will be able to develop a "reliable, easy to perform, inexpensive laboratory test" that could provide a diagnosis in about five days.

Biolog CEO Barry Bochner told BioArray News that the privately held Hayward, Calif.-based firm has provided GGC with technical advice and has made customized assay plates for Schwartz's lab containing the "most promising tests."

GGC isn't the only organization developing an array-based test for autism. For example, Salt Lake City-based Lineagen has already launched an Affymetrix-manufactured test, and plans to debut a second version later this year (see related story, this issue).

Schwartz said he chose to work with Biolog's Phenotype MicroArray platform because it "allows us to understand what is happening within the cell."

"How does the cell handle being subjected to a single energy source? Such information can provide valuable information as to what pathways are perturbed either as a result of a known single gene mutation or, in the case of ASD, what pathways are perturbed in patients exhibiting the same behavioral phenotype," said Schwartz. "Such information might possibly lead to simple treatment modalities."

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