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CR515S—Mini-Tutorial by Nancy Reinhold

Personalized Medicine: The Promise of PharmacogenomicsNancy Reinhold

A Swiss-born chemist named Johannes Friedrich Miescher first isolated a substance he callednuclein (later named nucleic acids) from white blood cells in the late 1860’s, but was unaware of its purpose. Approaching a full century after Miescher’s discovery, Oswald Avery, MaclynMcCarty and Colin MacLeod performed the experiments that, in 1943, revealed deoxyribonucleicacid (DNA) as the carrier of genetic information, a role assumed to be the work of a protein atthat time in history. Taking from the work of Rosalind Franklin and Maurice Wilkins, JamesWatson and Francis Crick published the molecular structure of DNA in a 1953 issue of

Nature

,thereby paving the way for the development of the biotechnology industry and precipitatingfurther evolution of modern genetics research. In 1990, the US Department of Energy and National Institutes of Health officially launched the Human Genome Project with an aim to mapthe entire human genetic blueprint. More than a decade later, this project culminated in the publication of the complete sequencing of all twenty-four human chromosomes by 2003

.From the extensive databases generated in the collaborative effort of the Human Genome Project,we stand to advance our understanding of the role of genes in innumerable metabolic pathwaysand biochemical processes as well as achieve greater insight into genetic risk factors for disease.This expanded knowledge brings with it a possibility of personalized medicine or pharmacogenomics--predicting how individuals will respond (or not) to various drug therapies based on their genetic makeup. This paper will explore the concept of personalized medicine byexplaining how pharmacogenomics may revolutionize healthcare and what potential impact itmay have on the conduct of clinical trials. Additionally, examples of current pharmacogenomic breakthroughs will be discussed along with a brief appraisal of the potential hurdles to making personalized medicine a reality.

Basis of personalized medicine and its potential

The safety and efficacy of drugs can be influenced by numerous factors, including lifestyle, age,environment, diet, health status and concomitant use of other medicines just name a few. Beyondthese factors,

there is also a genetic basis for the proper function of pharmaceuticals and how they are processed in the body

. Single nucleotide polymorphisms or “SNPs” are often mentionedwhen discussing pharmacogenomics. A SNP refers to substitution of a single nucleotide in the base pair sequence of a gene that may impact the function or expression of the gene. They occur throughout the human genome at frequency of about 1 per 1000 base pairs

(to learn more about

CR515S—Mini-Tutorial by Nancy Reinhold

SNPs, an illustrated tutorial can be found athttp://www.genome.gov/Pages/Education/DNADay/TeachingTools/MakingSNPsMakeSense.html.) Genetic polymorphisms, defined as “a variation in DNA that is too common to be due merelyto new mutation,”

can influence drug efficacy or toxicity through variation in cell signaling, drugreceptors, drug transporters and drug metabolism.

Currently, doctors choose which medications to prescribe for their patients based on their overall familiarity with different medications, which they may have gained through their ownclinical experience or through education by various other means.

As one article puts it, “thefinal choice of medications remains empirical, if not arbitrary, for the great majority of patients.”

Ultimately, the clinician does not know in advance if the drug they prescribe will have the desiredeffect or if perhaps the patient may even have an adverse drug reaction. It is in this clinicaldecision that the potential of pharmacogenomics is most greatly valued.One

major focus of pharmacogenomics is determining which genes affect the action or bioavailability of drugs, understanding gene function in key biochemical pathways and theimpact of variation in those genes

. Increased knowledge about the effects genes have onabsorption, distribution, metabolism and/or excretion of medicines could guide treatmentdecisions by allowing predictions of effectiveness or toxicity in populations possessing a particular genetic profile. A patient’s genetic makeup may manifest as an enzyme deficiency that precludes the necessary conversion of a drug into its active forms within the body, rendering thedrug ineffective. Conversely, the patient’s genotype may be such that they metabolize the drugtoo quickly such that standard dosing is not effective, thus requiring the patient to receive larger doses in order to achieve a therapeutic level of the drug. Yet another scenario is when the patientfails to excrete drug metabolites appropriately, leading to accumulation of chemicals that aretoxic and giving rise to a serious adverse reaction to the medication.

Through greater understanding of the relationships between gene function and pharmacokinetics, physicianscould avoid administering a drug that is unlikely to benefit a patient, modify dosing regimensto improve effectiveness of the treatment and limit toxicity or adapt their strategy for patient care

(e.g. more closely monitor patients known to have a higher risk of adverse drug reaction).In addition to enhancing our ability to predict drug response, pharmacogenomics also offers amore directed approach to drug development.

Understanding the mechanism of disease asdictated by gene expression enables the identification of targets for therapy and aids basicresearch into the development of products that are anticipated to have specific action in critical

CR515S—Mini-Tutorial by Nancy Reinhold

steps of pathogenesis

. Not only is this kind of information significant for improving the ability totreat existing disease, but through this advanced learning, an individual’s predisposition to certainillnesses might be revealed, allowing opportunity to take preemptive measures that would delayor prevent onset of disease. It may even be possible to institute early treatments that interrupt the progression to disease rather than merely reacting after symptoms manifest when the illness mayalready be in advanced stages.

Modern-day examples of personalized medicine

While the advantage of pharmacogenomics may seem like something that will only be attained inthe distant future, there are already a number of examples where personalized medicine has become a reality even if its application is still somewhat rudimentary. A review by Tsai andHoyme and a publication by McLeod and Evans list

∗

the following genes and the findings of eachgene’s effect on responses to certain drugs:

•

TPMT (thiopurine methyltransferase)

—

Individuals with inherited deficiency of TPMTexperience higher incidence of hematopoietic toxicity with standard dosing of azathioprine,mercaptopurine and thioguanine (drugs used to treat various conditions like rheumatoid arthritis,inflammatory bowel disease and childhood leukemia).

•

CYP2D6 (debrisoquin hydroxylase)

—

Patients with mutation causing low functioning of CYP2D6 have increased occurrence of side effects from certain drugs (e.g. clozapine, amiodarone,flecainide) used for psychiatric, cardiovascular and neurological conditions. Reduced activity has also been associated with ineffective analgesia with morphine.

•

ApoE4 genotype

—“83% of [Alzheimer’s] patients without an apoE4 genotype had an improvementin total response and cognitive response to tacrine therapy, compared with 40% in patients withapoE4”

Impact to pharmaceutical industry, regulatory agencies and healthcare

It is yet unknown just how extensively medical science will be reshaped by pharmacogenomics.One anticipated benefit is that safer drugs will more quickly become available while potentially being more cost-effective. If pharmacogenomics delivers on that promise, patients will surelyreap the rewards, but what are the ramifications for the pharmaceutical industry, regulatoryagencies and healthcare?

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The literature highlights other additional examples, but this list has been condensed to include the cases that were lesstechnically complex.