Personalized Medications
Pharmacogenomics is the study of how an individual's genetic inheritance affects the body's response to drugs. Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own genetic makeup. Environment, diet, age, lifestyle, and state of health all can influence a person's response to medicines, but understanding an individual's genetic makeup is thought to be the key to creating personalized drugs with greater efficacy and safety.

A 1998 study of hospitalized patients published in the Journal of the American Medical Association reported that in 1994, adverse drug reactions accounted for more than 2.2 million serious cases and over 100,000 deaths, making adverse drug reactions (ADRs) one of the leading causes of hospitalization and death in the United States.

Many drugs that are currently available are "one size fits all," but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Drugs are metabolized by genes known to vary within the population. Genetic variations that change the properties of enzymes that break down drugs or mark them for excretion can cause adverse drug reactions. Without knowing all of the genes involved in drug response, scientists have found it difficult to develop genetic tests that could predict a person's response to a particular drug.

Pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry with annotated knowledge of genes, proteins, and single nucleotide polymorphisms. Pharmacogenomics could also lower the cost of health care by decreasing the occurrence of adverse drug effects and increasing the probability of successful therapy.

The difference between pharmacogenomics and pharmacogenetics is:
● Pharmacogenomics refers to the general study of all of the many different genes that determine drug behavior.
● Pharmacogenetics refers to the study of inherited differences (variation) in drug metabolism and response.
● The distinction between the two terms is considered arbitrary and now the two terms are used interchangeably.

With the current way of dispensing medications, some patients are given medications that either don't work or have bad side effects. Often, a patient must return to their doctor over and over again until the doctor can find a drug that is right for them. By using a patient's genetic make-up, doctors will be able to make more accurate diagnoses, and prescribe more efficient drug therapies with fewer adverse side effects. After a simple and rapid test of ones DNA, doctors can change their mind about a drug that is considered for a patient because their genetic test indicates that they could suffer a severe negative reaction to the medication. Then upon further examination of their test results, the doctor may find that they would benefit greatly from a new drug on the market, and that there would be little likelihood that they would react negatively to it.

The University of Utah Genetic Science Learning Center web site http://learn.genetics.utah.edu/ has some very good educational tools regarding genetics that can help those who aren't scientists or doctors to understand the many of the aspects of genetics. In this case they have a section regarding personalized medications at http://learn.genetics.utah.edu/content/pharma/ but they also have many other topics that are of interest in multiple sclerosis (MS) research that are worth looking at. They have animations (in the above links) that are very good at describing visually the different aspects of their research.

Another site that was worth looking into was SNPs: Variations on a Theme, a Science Primer from the National Center for Biotechnology Information (NCBI). A recent change to the NCBI website has caused this page to no longer be available. We have, however, managed to locate the specific page and have it as it was on our site. You can view it by going to this link.
Single Nucleotide Polymorphisms (SNPs)
Single nucleotide polymorphisms (SNPs) are deoxyribonucleic acid (DNA) sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered. For example, an SNP might change the DNA sequence AAGGCTAA to ATGGCTAA. For a variation to be considered an SNP, it must occur in at least 1% of the population. SNPs, which make up about 90% of all human genetic variation, occur every 100 to 300 bases along the 3-billion-base human genome. Two of every three SNPs involve the replacement of cytosine (C) with thymine (T). SNPs can occur in coding (gene) and noncoding regions of the genome. Many SNPs have no effect on cell function, but researchers believe others could predispose people to disease or influence their response to a drug.

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image info This image is courtesy of the Genetic Science Learning Center, University of Utah, http://learn.genetics.utah.edu/.
It is strictly for educational, non-commercial use.

For SNPs to be used in this way, a person's DNA must be examined or sequenced for the presence of specific SNPs. The problem is that traditional gene sequencing technology is very slow and expensive and has therefore impeded the widespread use of SNPs as a diagnostic tool. DNA microarrays (or DNA chips) are an evolving technology that should make it possible for doctors to examine their patients for the presence of specific SNPs quickly and affordably. A single microarray can now be used to screen 100,000 SNPs found in a patient's genome in a matter of hours. As DNA microarray technology is developed further, SNP screening in the doctor's office to determine a patient's response to a drug, prior to drug prescription, will be commonplace.

Identifying SNPs in the human genome

Researchers approach of identifying, cataloging and characterizing SNPs in two main ways:

Genomic approaches - This approach is used by researchers who want to see the big picture. Several large-scale projects have combined the efforts of many institutions to identify and catalog all of the SNPs in the 3-billion-base pair human genome. Researches compare the genomes of numerous individuals to identify the differences.

Functional approaches - This approach is used by researchers who are interested in a particular disease or drug response. The biological processes involved in diseases and drug responses are controlled by the activities of many genes. Researchers interested in a particular process select genes known to be involved in the process and examine them in people who have a response or disease, as well as those who don't. By comparing people's DNA sequences, scientists can identify SNPs that correspond with a particular function or response.

SNPs may fall within coding sequences of genes, non-coding regions of genes, or in the intergenic regions between genes. SNPs within a coding sequence will not necessarily change the amino acid sequence of the protein that is produced, due to degeneracy of the genetic code. A SNP in which both forms lead to the same polypeptide sequence is termed synonymous (sometimes called a silent mutation) — if a different polypeptide sequence is produced they are nonsynonymous. A nonsynonymous change may either be missense or nonsense, where a missense change results in a different amino acid, while a nonsense change results in a premature stop codon. SNPs that are not in protein-coding regions may still have consequences for gene splicing, transcription factor binding, or the sequence of non-coding RNA.
Drug Development Today and Tomorrow
The constant increases in the cost of prescription drugs has made it difficult for many to afford the medications that they need. Thanks to modern medicine, our lifespan and quality of life continue to improve. This, however, creates a new problem in that our aging population now requires an ever-increasing amount of new medications. The current drug discovery process is time consuming and expensive. Once a drug is approved, it has taken many years and cost millions of dollars in research.

The future holds the hope that instead of making an educated guess about what medication to prescribe for a patient, a doctor may use a genetic test to indicate which medication the patient would respond to best. Such tests could also be used to determine if a patient is among those who might suffer severe side effects from a certain drug. Pharmacogenomics, the study of how genetic variations affect the ways in which people respond to drugs, may make this possible.

Pharmacogenetic approaches might make this process more efficient by enabling researchers to:
● Identify genes involved in disease
● Understand how genes and the proteins they produce are affected by various drug candidates
● Effectively choose target populations to be used in clinical trials
Anticipated benefits of pharmacogenomics
● More Powerful Medicines
Pharmaceutical companies will be able to create drugs based on the proteins, enzymes, and RNA molecules associated with genes and diseases. This will facilitate drug discovery and allow drug makers to produce a therapy more targeted to specific diseases. This accuracy not only will maximize therapeutic effects but also decrease damage to nearby healthy cells.
● Better, Safer Drugs the First Time
Instead of the standard trial-and-error method of matching patients with the right drugs, doctors will be able to analyze a patient's genetic profile and prescribe the best available drug therapy from the beginning. Not only will this take the guesswork out of finding the right drug, it will speed recovery time and increase safety as the likelihood of adverse reactions is eliminated. Pharmacogenomics has the potential to dramatically reduce the estimated 100,000 deaths and 2 million hospitalizations that occur each year in the United States as the result of adverse drug response.
● More Accurate Methods of Determining Appropriate Drug Dosages
Current methods of basing dosages on weight and age will be replaced with dosages based on a person's genetics --how well the body processes the medicine and the time it takes to metabolize it. This will maximize the therapy's value and decrease the likelihood of overdose.
● Advanced Screening for Disease
Knowing one's genetic code will allow a person to make adequate lifestyle and environmental changes at an early age so as to avoid or lessen the severity of a genetic disease. Likewise, advance knowledge of a particular disease susceptibility will allow careful monitoring, and treatments can be introduced at the most appropriate stage to maximize their therapy.
● Better Vaccines
Vaccines made of genetic material, either DNA or RNA, promise all the benefits of existing vaccines without all the risks. They will activate the immune system but will be unable to cause infections. They will be inexpensive, stable, easy to store, and capable of being engineered to carry several strains of a pathogen at once.
● Improvements in the Drug Discovery and Approval Process
Pharmaceutical companies will be able to discover potential therapies more easily using genome targets. Previously failed drug candidates may be revived as they are matched with the niche population they serve. The drug approval process should be facilitated as trials are targeted for specific genetic population groups --providing greater degrees of success. The cost and risk of clinical trials will be reduced by targeting only those persons capable of responding to a drug.
● Decrease in the Overall Cost of Health Care
Decreases in the number of adverse drug reactions, the number of failed drug trials, the time it takes to get a drug approved, the length of time patients are on medication, the number of medications patients must take to find an effective therapy, the effects of a disease on the body (through early detection), and an increase in the range of possible drug targets will promote a net decrease in the cost of health care.
Barriers to pharmacogenomics progress
● Complexity of finding gene variations that affect drug response
Single nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered. SNPs occur every 100 to 300 bases along the 3-billion-base human genome, therefore millions of SNPs must be identified and analyzed to determine their involvement (if any) in drug response. Further complicating the process is our limited knowledge of which genes are involved with each drug response. Since many genes are likely to influence responses, obtaining the big picture on the impact of gene variations is highly time-consuming and complicated.
● Limited drug alternatives
Only one or two approved drugs may be available for treatment of a particular condition. If patients have gene variations that prevent them using these drugs, they may be left without any alternatives for treatment.
● Disincentives for drug companies to make multiple pharmacogenomic products
Most pharmaceutical companies have been successful with their "one size fits all" approach to drug development. Since it costs hundreds of millions of dollars to bring a drug to market, will these companies be willing to develop alternative drugs that serve only a small portion of the population?
● Educating healthcare providers
Introducing multiple pharmacogenomic products to treat the same condition for different population subsets undoubtedly will complicate the process of prescribing and dispensing drugs. Physicians must execute an extra diagnostic step to determine which drug is best suited to each patient. To interpret the diagnostic accurately and recommend the best course of treatment for each patient, all prescribing physicians, regardless of specialty, will need a better understanding of genetics.
Challenges and Issues
Pharmacogenetics has great potential to advance medical treatment and drug discovery. With advances in these fields will come technical and economic challenges, as well as ethical issues:
● Genome analysis for all individuals
Rapid, automated methods must be developed to efficiently identify SNPs in the three-billion-base-pair genome that influence susceptibility to disease and individual drug response.
● Studying the biology of genes involved in disease and drug reactions
It can take decades to study a gene's product, function and association to drug response.
● New techniques need to prove their worth
SNP analysis and expression profiling are in their infancy, and few success stories exist.
● Complex diseases really are complex
In reality, disease and drug response can involve hundreds of genes. Environmental factors such as age, nutrition and lifestyle can influence disease and drug response as well.
● Adopting new practices in healthcare
Health care providers and pharmacists will have to become educated about new diagnostic tests and how to use them when treating and advising patients.
● Who will pay for it?
Today's methods for SNP analysis and expression profiling are expensive. Health insurance companies may not want to pay for extra diagnostic tests, and economic issues might influence which drugs pharmaceutical companies choose to develop.
● Ethical and privacy issues
Identified genetic susceptibility to disease may have implications for employers and insurance companies. Who will have access to genetic information and databases?