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Startup Behavioral Diagnostics Wins SBIR Grant to Develop Smoking Cessation Methylation Assay

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NEW YORK (GenomeWeb) — Iowa City-based Behavioral Diagnostics recently won a one-year, $200,000 Small Business Innovation Research grant from the National Institute on Drug Abuse to fund development of its quantitative measure of cigarette smoking and cessation.

Based upon previous research of a particular methylation mark, the test will assay extent of remethylation of a site demethylated by cigarette smoking but not by nicotine replacement therapy.

In an interview with PCR Insider this week, co-inventor of the assay, Robert Philibert, a professor of psychiatry and director of the Psychiatric Genetics Laboratory at the University of Iowa, said the biomarker has been patented and developed into a quantitative PCR assay with the trademarked name Smoke Signature. Using bisulfite sequencing and real-time PCR, it measures DNA methylation in and around a site called cg05575921. This site captures half of all the differential methylation signals in GWAS studies of heavy smokers, he said.

Furthermore, in young smokers it captures an even larger portion of the variance and it is the first locus to respond to smoking via DNA methylation, Philibert said. This has led him to propose that pediatricians screen for nascent smoking using this marker, as recently published online in the journal Epigenetic Diagnosis and Therapy.

The differential methylation of the cg055 region can be measured in blood and saliva, and is specific to peripheral blood mononuclear cells, Philibert said.

"By looking at this locus we capture the most sensitive area in the genome," to both smoking and cessation, he said. The correlation has been validated by eight other studies, including some by outside groups. He added that RT-PCR analysis of this site has a 0.99 correlation coefficient with Illumina array data, as demonstrated in a BMC Genomics study published earlier this year. This enhances the validity of the genome-wide DNA methylation results, according to that study.

Philibert said that Behavioral Diagnostics intends to enroll patients in clinical trials of Smoke Signature soon. Specifically, using the Phase I SBIR funds, Philibert now plans to follow 50 smokers as they go through smoking cessation treatment.

Philibert is also working on a similar methylation-specific PCR assay to quantitatively measure alcohol consumption, and has a paper on this topic under revision at the moment, he said. "We're going to develop a set of qPCR markers for that as well," he added.

Only about five percent of patients who visit a doctor's office for smoking cessation actually wind up quitting, Philibert said. One of the reasons why is that doctors have been unable to quantify smoking behavior effectively.

Exhaled carbon monoxide is one common measure of cessation, but is only useful within 12 hours of smoking. Serum ELISAs for cotinine are a common measure, but take about a day, and are not informative in patients who use nicotine replacement therapy. Since up to 90 percent of patients who try to quit smoking use NRT, physicians often must rely on self-report to track patient success or failure, Philibert said.

Using Smoke Signature, a doctor can follow up with a patient who says he is quitting but whose methylation status remains unchanged. The doctor can ask, "Did I not explain how to use the medication, could you afford it, did you get that coupon, those sort of things," Philibert said. This will increase compliance and effectiveness of treatment.

As recently reviewed in Clinical Pharmacology and Therapeutics, there have been a number of studies on SNPs that predict quitting success rates, as well as proposed pharmacogenomic approaches to tailoring smoking cessation to patient genotype. However, Philibert was unaware of anyone developing a test for a biomarker of smoking itself that does not rely on exhaled CO or cotinine levels.

Philibert said he envisions availability of the test outside a doctor's office, allowing patients to order the test themselves through an online service. This could provide people who are trying to quit with feedback, or a measure of how they are doing as they transition into a non-smoking lifestyle and their DNA remethylates itself back to the levels of a non-smoker.

Pharmaceutical companies might be potential customers. Testing new nicotine replacement therapies and drugs also depends on self-report, which generates "noise" in clinical trials. "Here you have a quantitative measure to [determine] whether your drug is actually working," Philibert said.

Insurance companies could also be interested in Smoke Signature. Epigenetic signatures are fairly stable and emanate from the white blood cells. Patient DNA could be tested, even post-mortem or after blood transfusion, to verify whether a person quit as they claimed.

Behavioral Diagnostics is currently looking for venture capital and soliciting collaborators, Philibert said. Testing will move to Phase II this winter, and the assay may be commercially available by next spring. It is currently available for research use only.

The company will also be pursuing US Food and Drug Administration approval for the test. Although the assay is not technically diagnosing a medical disorder, approval will allow full access, Philibert said.

Children and young adults are especially responsive to behavioral interventions, but they may also be more likely to evade accurate self-report of smoking status. A quantitative test could provide pediatricians additional opportunities to intervene, which might help a young person avoid nicotine addiction and future negative health consequences.

"We're really quite confident that once this gets into pediatricians' hands, we'll be able to sell about a million of these kits a year," Philibert said. "And people will get better. That's the most rewarding part."

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