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If PGx is About Life, Why is Steven Wong Genotyping Death?

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At A Glance

Name: Steven Wong, professor of pathology, and director of clinical toxicology at Therapeutic Drug Monitoring and Pharmacogenetics at the Medical College of Wisconsin.

Age: 53

Background: PhD in chemistry; a board-certified toxicologist from the American Board of Clinical Chemists and Toxicology.

 

In a first-floor lab at the Medical College of Wisconsin, Steven Wong, a professor of pathology, works with the dead. Or at least he works with their DNA.

Wong is a member of a research group at the college that has pioneered a quietly growing field called molecular forensics: He and his team perform genotyping tests on the recently deceased to better understand the genetic basis for the many ways in which people respond to drugs.

These days, Wong’s study focuses on analgesia and may help pain-management specialists learn why certain patients respond well to narcotic and other kinds of therapies — and why other patients die. SNPtech Reporter caught up with Wong this week:

Tell me a little bit about your research.

Over the past four years, we have been exploring the clinical applications of pharmacogenomics for enhancing individualized drug therapy. One area we study is post-mortem toxicology. Specifically, we systematically evaluate the application of pharmacogenomics in the interpretation of drug toxicity in post-mortem settings, and we try to figure out whether or not genetics play a role in drug toxicity.

The second area we are beginning to be very good at is the use of pharmacogenomics for pain management. Often time, pain management is done with the like of Tylenol, and aspirin, and, before you know it, by COX-2 inhibitors.

Also, drugs like Prozac and gabapentin are also used for pain management. People respond differently to all of these drugs. So what we are saying is that we can use the tools of pharmacogenetics to determine how certain people will respond to these drugs.

What tools does your lab use in its research?

Initially, the current overall comprehensive approach uses systems biology. We try to recognize that the gene encodes an enzyme that metabolizes the drug. It also affects how the drug is being transferred around the body, and also the gene regulates the drug’ receptors.

In the first pass, we are primarily interested in genotyping patients for [cytochrome] P450 genes. A little bit further on we may be interested in genotyping their effector proteins or carrier proteins, or genes that encode those [response]. Then, in the final analysis, we are interested in genotyping the drug receptors.

We can see that the rational way of conducting pharmacogenetic research is by following the systems-biology approach.

Is there interest in your work among pharmaceutical or biotechnology companies? Have the makers or Tylenol or Celecoxib or Oxycontin been calling you non-stop?

Companies that make antidepressants have shown interest. They have not yet signed any research collaborations with us, but there has been some interest. As far as I can tell, many of the drug companies and pharmaceutical houses use the systems-biology approach so that they can better stratify patients according to their genotypes and to the various drug regimens.

Run me through a typical day in your lab. How would you work on a patient that presents to a collaborating physician’s office with the need for long-term analgesia?

First and foremost, this is not done clinically; this is still very much in the investigational stage. So for that we obtain IRB [institutional review board] approval to make sure that the research will not harm the patient. And because there is genetic testing, we need to maintain patient confidentiality.

Having done all that, the patient would then sign a consent form that says we are only going to do limited genotyping only for the purpose of pain management. In this particular case, we would only genotype the cytochrome P450 2D6 3, 4, ands 5, which accounts for over 95 percent of people who may be poor metabolizers of pain medicine.

Which pain medicine?

The pain medicine that we are looking at right now are drugs such as [Citalopram] and Prozac, and oxycodone and methadone.

How long has your group researched analgesics?

They’ve been doing this for the past three years now. We have experienced examples [in ourn research from] a very potent drug for the treatment of pain management called oxycodone — which has the brand name Oxycontin — which is rather notorious by now. The other one is a very, very, very good drug, but it is under-appreciated now: methadone.

Methadone is used for addiction, but it is a very efficacious analgesic. And those two drugs are both metabolized by P450 2D6. Therefore, we think that patients who may have taken that drug, if we can get their genotype ahead of time, then we might be able to know how to dose them.

Another area that we have begun to work in is to recognize addiction. Many drug addicts are treated with methadone. In the pharmacogenetics space, one study has already been published on the post-mortem work that we have done. We have compared the finding of patients who have died from oxycodone ingestion, versus the control population comprising people who are not taking oxycodone.

We found out that the preference of the poor-metabolizer in oxycodone death is higher than that of the normal population. In other words, we are beginning to hypothesize that [when] a person is genetically predisposed to be a poor metabolizer, they stand a higher risk of experiencing drug toxicity.

Has your group been working with pain-management specialists or anesthesiologists?

We are beginning to work with the pain-management specialists to look at the way those physicians use oxycodone and methadone as pain management. In this kind of research, we use patients who are already in the clinic, and we just have them sign a consent form saying that we are going to try to find out what kind of genotype you have.

These are patients who are given narcotic analgesics as pain management; they’re not addicted. Although there’s a fine line there (laughs).

Different patients become addicted to their analgesia at different stages, and this is where your research comes in: to determine those patients are more likely to become addicted more quickly as a result of poor metabolization?

Exactly.

Let’s talk about your post-mortem research. How exactly do you perform genotyping studies on decedents?

First of all, we get IRB approval; we work with selected cases that are certified as being an oxycodone or methadone death. It is important to recognize that these people were not specifically drug abusers. Rather, they have been certified to have had oxycodone or methadone on board at the time of death.

Next, we take a small amount of [the] whole blood left over from an autopsy, and we do a DNA extraction. Then we do the PCR, and we identify the gene by using a combination of techniques, such a conventional RFLP, or the real-time PCR. Then we look at each of the mutations.

Results from these studies will tell us whether the person is normal — whether he is a wild-type, like you and I …

Hopefully …

… or a person who might be an intermediate metabolizer in whom one of the two chromosomes has mutations. Or, the person is a poor metabolizer, whereby both chromosomes have the same mutations, which means that they lack the ability to adequately metabolize drugs.

This research is not meant to be definitive; rather, it is designed to add to the overall interpretation of what … circumstance surrounded a death. It also adds to the comfort level to the family and to the pathologist as they make a declaration of death.

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