How Pharmacogenomics Hopes to Improve the Treatment of Cerebral Creatine Deficiencies

How Pharmacogenomics Hopes to Improve the Treatment of Cerebral Creatine Deficiencies

Kim Tuminello, Director of Advocacy for ACD, recently sat down with Dr. Ruben Bonilla Guerrero, who is the Medical Director of Medical Affairs for Admera Health, to talk about his professional background, his current position, and how pharmacogenomics (PGx) could possibly help the CCDS community.

Kim: Can you tell us a little bit about yourself, and your background? 

Ruben: I was born in Mexico City and raised in Veracruz, Mexico. I am a physician by training. I obtained my MD at the Universidad Veracruzana in Veracruz, Mexico. I trained in three medical specialties at the Mayo Clinic in Rochester, Minnesota – Experimental Pathology, Clinical Pharmacology (with a subspecialty in Pharmacogenomics and Vaccine Development), and Clinical Biochemical Genetics.

 I am boarded in Clinical Biochemical Genetics by the American Board of Medical Genetics, and in Molecular Biology by the American Society of Clinical Pathologist. I am a Fellow of the American College of Medical Genetics, a Fellow of the American Association of Clinical Chemistry. 

After 14 years at the Mayo Clinic, I joined Quest Diagnostics, Inc. in San Juan Capistrano, California, for almost ten years, where I served as the Associate Medical Director for the Department of Genetics, and the Medical Director of Medical Affairs for the Department of Genetics. There, I was able to use all of the knowledge I gained during my academic center years, and apply them to the everyday world, to make it accessible to everyone.

My training, way of thinking, and life experience has equipped me with identifying many ways to help in treating patients with metabolic disorders and cancer. Because of that, I decided to join a company specialized in personalized medicine, such as Admera Health.

Kim: Can you tell us about PGx, and how you think it could help?

As you know, the creatine biosynthesis disorders (CBD) (deficiency of arginine:glycine amidinotransferase (AGAT), guanidinoacetate methyltransferase (GAMT), both autosomal recessive and the X-linked defect of the creatine transporter (SLC6A8)) are inherited energy production disorders of creatine synthesis. Deficiencies in any of these metabolic steps disrupt energy metabolism of the cells, resulting in a depletion of cerebral creatine as well as in other tissues such as muscle. Common symptoms include cognitive disability, speech and language delay, gastrointestinal manifestation, cardiovascular manifestation, autistic-like behaviors, and epilepsy.

Ruben asked: Does the following scenario sound familiar to you?

A patient starts having seizures, is immediately put on antiseizure medications, and after several visits to physicians, is finally diagnosed with creatine biosynthesis disorder via the proper biochemical and molecular genetics tests. However, the seizures didn’t go away even after trying several anti-seizure medications.

Have you ever wondered why a medication works very well for some patients, but it doesn’t work for other patients, and sometimes makes things worse by also producing adverse drug reactions?

Ruben explained that an important factor in drug response is the direct correlation between an individual’s gene versions (genotype) regulating drug metabolism (pharmacokinetics) and the function of the biological targets where medications exert their effect (pharmacodynamics). When studied together, it is called pharmacogenomics (PGx).

Like the pathways that control our metabolism and receptors that regulate how we respond to compounds (like serotonin) we make, we have metabolic pathways that control how we metabolize every medication we take and receptors where the drugs we take (like serotonin reuptake inhibitors) have their effect.

Medications used to treat the symptoms of cerebral creatine deficiencies such as antiepileptics, psychotropics, neuroregulatory medications, anti-pain medications, cardiovascular medications, and gastrointestinal medications come in two different forms:

  1. Active drugs (drugs that have their therapeutic effect as they are taken or given).
  2. Pro-drugs (drugs that require bio-conversion to an active form to have the desired therapeutic effect).

A functional decrease or increase of any of these processes, or a reduction of affinity between the medication and its target, will result in reduced efficacy and potential adverse drug reactions.

The treatment of an inborn error of metabolism, in general, expands into two clinical areas:

  1. A very focused approach to address the specific metabolic derangement (substrate reduction/product supplementation, enzyme replacement therapy, chaperone replacement therapy, substrate replacement therapy, and gene therapy).
  2. The treatment of the associated symptoms to reduce the different manifestations produced by a metabolic disorder, which still follows the traditional and historical empirical success/fail “one size fits all” therapeutic method.

The latter approach leads to a delay in mitigating symptoms and prolonged clinical manifestation due to the lack of medication efficacy and an increased risk of adverse drug reactions. This combination produces a lack of the patient’s adherence to therapeutic measures, continuous modifications of the patient’s therapeutic regimen to find the correct medication and dose, and an overall increasing cost of healthcare.

Kim: How do you go about getting PGx testing ordered and done?

The test needs to be ordered by a physician, nurse practitioner, and in some states, by a PharmD. There are many pharmacogenomics tests available and the test should include genes beyond drug metabolism (pharmacokinetics) and drug targets (pharmacodynamics). It should include genes related to specific adverse drug reactions and efficacy. And finally, it should contain certain Mendelian conditions for which there is specific treatment.

Kim: How many genes, medications, and what type of drugs does it cover?

The test should include genes beyond drug metabolism (pharmacokinetics) and drug targets (pharmacodynamics). It should include genes related to specific adverse drug reactions and efficacy. And finally, it should contain certain Mendelian conditions for which there is specific treatment.

The test report should cover medications in as many therapeutic areas as possible, as the patient should be treated as a whole.

KimWhat type of support should the ordering healthcare provider or the patient get after ordering the test?

Make sure the laboratory has pharmacogenomics experts in their leadership who should always be available to provide support — ideally, an MD, PharmD, or Genetic Counselor with formal pharmacogenomics training.

Kim: How is testing done?

There are several different PGx test collection methods that are available for you to choose from:

  1. Buccal Swab
  2. Saliva
  3. Mouthwash
  4. Blood

The patient’s DNA is isolated and analyzed while only looking for specific genes related to pharmacogenomics.

Kim: Would my insurance cover pharmacogenomics testing?

Ruben said, “sometimes yes, more and more insurance companies are paying for this type of testing, either Medicare, in some state Medicaids, and usually as part of your plan-specific, commercial PPO with out-of-network benefits, but you would need to check with your own insurance to make sure. Personalized medicine using PGx aims to guide the patient’s treatment, by aiding in medication selection based on the patient’s results towards medications, with the highest level of efficacy and the least likelihood of adverse side effects.


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