The Future of Personalized Medicine

Michael D. Kane, PhDAssociate Professor, University Faculty Scholar

Department of Computer and Information TechnologyCollege of Technology

Lead Genomic Scientist, Bindley Bioscience Center at Discovery ParkPurdue University

West Lafayette, Indiana 47907

bioinformatics.tech.purdue.edu

At the current rate of genomic sequencing worldwide, a new gene sequence is derived every 1.5 seconds!

…equivalent to about 600 DNA base pairs every second of every day!

Single Nucleotide Polymorphisms (SNPs) are simple changes (or differences) in the DNA sequence that may have little or no impact on human health. They represent 90% of all human genetic variations.

Genetically similar to a mutation, but distinct in that a SNP is not causal to a clinical disease or disorder.

Genetic Variance

Genetic Variance

Modern drug discovery & development falls outside the tolerances & toxicity that have resulted from evolution, because most of these compounds have NEVER been seen in nature, and natural-based pharmaceuticals are concentrated and enriched for dosing purposes.

Important Consideration: Inheritance

The appearance of deleterious mutations during evolution tend to NOT be inherited for obvious reasons (those that affect growth, reproduction and viability).

…and our modern existence is the result of millions of years of tolerated (and occasionally beneficial) changes in our genome, which is most often evident in what natural products we can and cannot eat or consume (think: evolutionary pressure & natural selection)

Monomethyl Hydrazine (in “False” Morel Mushrooms)(there are many examples of “toxins” in nature, many of themare presumably synthesized to prevent consumptionor predation of the host plant or organism)

Tylenol: Acetaminophen (Cats?)

Genetic Variance

Our Genome is derived from our surviving ancestors through selective pressure.

Natural Products vs. Modern Pharmaceuticals

Differences in our genome and our response to these compounds

Natural Selection vs. Modern Life Span

I am the 10th generation, you are the 11th generation of humans on this planet with an average life span >40 years old!

More than 770,000 patients die or sustain serious injury every year in the U.S. from Adverse Drug Reactions (ADRs).

ADRs are typically the 5th leading cause of death in the United States and are one of the leading, preventable public health issues today.

In terms of total health care dollars, ADRs cost the U.S. health care system between $1.5 and $5.4 billion per year.

It is estimated that human genetic variation (SNPs) have been account for approximately 30% of all ADRs.

Adverse Drug Reactions

Pharmacogenomics and Personalized Medicine

Pharmacogenomics involves genetic differences in the human population that alter the safety and efficacy of drugs (from the “normal” or “typical” patient).

For the healthcare consumer, most of these genetic differences have an effect on (1) drug metabolism (pharmacokinetics) or (2) drug action (pharmacodynamics).

Personalized Medicine involves understanding how some genetic markers impact drug safety and efficacy, and PREDICTING how a patient will respond to a specific drug/dose (based on the patient’s genetic profile).

Pharmacogenomics and Personalized Medicine

Drug Metabolism and Personalized Medicine: Oxidative enzymatic “breakdown” of the dosed drug, primarily in the liver.

1)Normal Metabolism: The drug is cleared from the body at the rate established by the pharmaceutical manufacturer.

2)Ultra Metabolism: The patient harbors a genetic allele that INCREASES the rate of drug metabolism and clearance.

3)Poor Metabolism: The patient harbors a genetic allele that DECREASES the rate of drug metabolism and clearance.

Pharmacogenomics and Personalized Medicine

1 in 5 people harbor a SNP that alters the drug metabolism or drug activity of at least one FDA approved drug.

The effect of this genetic variation in the population does not always represent a serious risk to the patient, but may effect patient compliance and other “side effects” related issues that negatively impact health outcomes.

Pharmacogenomics and Personalized MedicineWarfarin (Coumadin): Anticoagulation. EXAMPLE: If you are prescribed WARFARIN, you have a condition that may generate potentially life-threatening blood clots. If you are dosed with too much WARFARIN you could experience serious complications due to internal bleeding, yet if you are dosed with too little WARFARIN you may be in danger of serious consequences associated with circulating emboli due to excessive blot clotting.

Warfarin Metabolism (hepatic)

CYP2C9 to 6-hydroxywarfain

Warfarin Drug Action (circulator system)

Vitamin K Epoxide Reductase Complex 1 (VKORC1) Inhibitor

Pharmacogenomics and Personalized MedicineGENESCRIPTION was developed as an educational tool that models the FUTURE of applied personalized medicine.

The online portal models a drug dispensing environment (pharmacist) where the user is presented with a patient that has:

1)DNA screened to identify any SNPs related to drug safety and efficacy.

2)Prescribed a drug that is affected by a SNP related to drug safety and efficacy.

3)Provides predictive information regarding the safety and efficacy of the prescribed drug in the patient.

www.genescription.com

Genescription is a free, online instructional utility available to the public, and can be accessed and utilized by anyone with an internet connection.

Dosing curve of a 10 mg oral dose in a “normal” metabolizer

From: www.genescription.com

Dosing curve of a 10 mg oral dose in a “poor” metabolizer

From: www.genescription.com

Dosing curve of a 10 mg oral dose of Warfarin in a “poor” metabolizer

From: www.genescription.com

Dosing curve of a 10 mg oral dose of Warfarin in a VKORC1-SNP Patient

From: www.genescription.com

Additional Items:

1) Genescription.com

2) P450 drugs, enzymes, and alleles

3) 23andme.com