Genomically Directed Medicine Using Genetic Profile to Tailor Better Drug Treatment

Mar 04, 2014 at 12:00 am by admin


The concept of individual genetic testing to tailor the best type of medicine and treatment for patients is no longer just theoretical. Precision or personalized medicine using genetic testing for diagnosis and treatment of patients is now available and being used often in Arkansas.

“The take home message is that the time is now,” said Bradley Schaefer, MD, division chief of the University of Arkansas for Medical Sciences (UAMS) Medical Genetics Division, who also practices at the Arkansas Children’s Hospital. “It is amazing what can be done. This technology has moved out of the research lab and can be applied in clinics to help people. It is unbelievable what it does for children we see who in the past we would never have known what was going on. It happens almost every day in my clinics now.”

Although commonly referred to as genetic or precision medicine, Schaefer prefers the term “genomically directed medicine” better because it is more specific about using genetic information to direct treatment.

The concept is what has been known intuitively for a long time: people are different. Some people are more sensitive to certain medications, and other are less sensitive. Some patients won’t be helped by a medicine that is a lifeline to others.

Arkansas has more people working in the area of precision medicine than most states with eight or nine researchers including clinical geneticists and molecular geneticists working at UAMS.

“We are moving out ahead,” Schaefer said. “We are being pretty proactive on this and setting up these really novel programs.”

Progress in the field has meant today’s genetic testing is far less expensive than in the past. The federally funded human genome product that sequenced the whole genetic code completed in 2001 took 13 years and cost $13 billion.

“Now we can do the same thing for $15,000 to $20,000 and get it done in about six months,” Schaefer said. “The positive side is that it is absolutely fascinating, the whole idea of knowing what is going on with genetic material and using it to improve treatments and health. The other side of the coin is that the information could be pretty darn scary. What if I find I have colon cancer risk? Could this information be used against me by insurers and employers? We don’t jump into tests without covering all the aspects of it with a patient.”

Genetic tests are not always covered by insurance.

“The tests are relatively expensive,” Schaefer said. “We have to work with each patient to learn if it is going to be covered and if not, do they still want it. Third party payers are just starting to learn about it. It is like other technologies like laptop computers. Prices will continue to get less expensive.”

Often people have a specific medical question in mind when undergoing genetic testing, and then there are those who are medically curious. One practical application is finding out how your specific gene type reacts to medications. The FDA currently has 155 medications that have been studied for how genetics will influence the drug.

The applications are of particular interest in psychiatry. A precision psychiatry program being established at the UAMS Psychiatric Research Institute (PRI) involves a multi-disciplinary team that includes Schaefer, Jeffrey Clothier, MD, medical director, UAMS Psychiatric Research Institute, Jennifer Hunt, MD, chair of the UAMS Department of Pathology, William Bellamy, MD, and Charles Sailey, MD, of the laboratory medicine molecular pathology group, and Elvin Price, MD, UAMS Pharmacy School.

“The central dilemma of psychiatry is selecting a treatment for the individual patient,” Clothier said. “The diagnostic schemes of DSM IV and now DSM 5 are silent about causation of these syndromes. The assumption that all patients with a particular DSM diagnosis have the same pathophysiology is certainly no more correct than the premise that all patients with a cough have the same pathophysiology.”

It is readily apparent that there are several contributors to depressive illness. This may explain why so many patients fail to respond to the initial treatment provided.

“At the current time, the majority of treatments for depressive illness are biological in nature,” Clothier said. “In general, one third of patients respond to the initial medication trial, another one third respond partially, and a full one third have little to no response. Said another way, two thirds of patients with significant depressive syndromes fail to respond completely to the initial medication. Many patients will fail multiple trials of medications.” Precision psychiatry attempts to identify factors that may predict treatment response, clinical course, and side effects of treatment. Previous attempts to do so were primarily based on clinical\behavioral subtypes of depression, melancholic depression vs. reactive depression for instance.

“This was somewhat useful, but still created a situation where a patient may not have received a full response to the treatment,” Clothier said. “Even before the complete human genome was sequenced, researchers found markers that related to treatment response. Some markers are related to the stress response such as the dexamethasone suppression test. Others have studied functional imaging to identify predictors of treatment response.”

There are dozens of studies that have identified candidate genes for predicting treatment response. At PRI they have begun to harvest some of this research.

“Over the past two to three years, we have used a commercially available genotyping service that looks at 11 gene markers and found that it was helpful in explaining a number of patients’ failure to respond and selecting specific changes in their regimen,” Clothier said. “However, the genes selected are a minority of the genes that have been identified in replicated studies. For this reason, we have selected a group of 40 genes from the literature that we believe are actionable. In other words, we believe knowledge of the individual’s genotype on these genes will inform and influence the treatment of the patient. The gene array is being built and tested and until it is ready for clinical use, we will rely on the limited commercially available products when necessary.”Clothier said the information provided by the individual’s genotype is not diagnostic or deterministic of outcome. It provides part of the biologic context of the patient’s suffering. Psychotherapy such as cognitive and behavioral therapy is still important.

“Other markers such as markers of the immune system and fMRI will likely be the next step in precision psychiatry as we move forward to extend biomarker evaluation to other conditions,” Clothier said. “I would expect that we will likely be able to find genotypes related to severe side effects for specific medications that will avoid the trial and error approach.”

There are only a couple of commercially available genetic testing products. The PRI uses one that costs about $700. Some insurance companies have paid for it while others decline payment as ‘experimental.’

“Another product has a different set of genes and prices at $3,800,” Clothier said. “I have not been convinced that this is a price point where I can say it is cost effective. Both services provide a genotyping of the principle enzymes related to medication metabolism. This can be useful information for a variety of non-psychiatric conditions. Our current plan is to provide a separate genotyping for more of the genes related to drug absorption, distribution, metabolism and elimination.”

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