PharmacogenomicsTina LinProfessor Douglas BrutlagBiochem118Adverse Drug Reaction Severe negative reaction to a prescribed drug 1994: more than 2.2 million serious cases andover 100,000 deaths by ADR Made ADRs one of the leading causes of hospitalizationand death in the U.S. Can’t determine how each individual will respondto a medication Drugs use the “one size fits all” system Suits only the “average” patientAdverse Drug ReactionProblem:one size does NOT fit allProbable solution:pharmacogenomicshttp://www.som.soton.ac.uk/staff/tnb/paindb/analyses/2001/PAINDB200110.JPGBackground Responses to drugs (positive and negative) arecomplex traits influenced by many different genes Hard to develop genetic tests to predict drug responsewithout knowing all the genes People’s gene show small variations in their nucleotidecontent made genetic testing for predicting drugresponse possible Most of human genome are identical, varies insingle nucleotide polymorphisms (SNPs or “snips”):DNA sequence variations that occur when a singlenucleotide in the genome sequence is altered Occurs once every 1,000 base pairs along the 3-billion-base human genomeDefinitions Pharmacogenomics: general study of allthe genes that determine drug behavior Pharmacogenetics: study of inheriteddifferences in drug metabolism & responseWhat is Pharmacogenomics? Combination of human genome knowledge (genes,proteins, SNPs) and pharmaceutical sciences(biochemistry, medicines) Examines inherited variations in genes that dictatedrug response Explores ways these variations can be used topredict whether a patient will have a good/bad/noresponse to a drug Ultimately, researchers hope to be able tocustomize drug therapies for specific patientpopulations or even individualsCurrent Uses Cytochrome P450 (CYP) family of liver enzymes Responsible for breaking down more than 30 differentclasses of drugs DNA variations in genes ability to metabolize drugs Inactive forms of CYP enzymes cause drug overdose Clinical trials researchers: use genetic tests for variationsin cytochrome P450 genes screen and monitorpatients Pharmaceutical companies: screen chemical compounds analyze how well they are broken down by variantforms of CYP enzymeshttp://quanta.synchem.kyoto-u.ac.jp/bioquant/images/p450.jpgCurrent Uses TPMT (thiopurine methyltransferase) Important in chemotherapy treatment of a commonchildhood leukemia breaks down a class of therapeuticcompounds called thiopurines Some Caucasians have genetic variances that preventthem from producing an active form of thiopurines Since the inactive form of TMPT cannot break down the drug,thiopurines elevate to toxic levels in the patient Doctors use this genetic test to screen for this deficiency TMPT activity is monitored to determine appropriatethiopurine dosage levelsCurrent Uses Cardiovascular pharmacogenetics Goals: to guide cardiovascular drug development and selection to optimize therapeutic benefit to minimize the potential for toxicity Researchers are exploring differences in the efficacy andefficiency of these cardiovascular drugs (regardless ofdrug concentration) based on common genetic variations(polymorphisms) will become prominent in the future e.g. antiarrhythmic, reninangiotensin, beta-blocker, lipid-lowering, and antithrombotic classesBenefits More effective medicines Can create drugs based on proteins, enzymes,and RNA molecules Facilitated drug discovery Therapy targeted to specific diseases Decrease damage to healthy cells “Right” drugs the first time: No more trial-and-error; process: analyze patient’s genetic profile prescribe best available drug therapy Speedy recovery; increase in safetyBenefits More appropriate drug dosages Current bases for appropriating dosage: Weight and age With pharmacogenetics: Based on genetics Maximizes therapy value; decreases over dosage Advanced screening for diseases Decide on lifestyle and adapt to environmentalchanges early on to avoid and/or lessen theseriousness of genetic diseases Allows for careful monitoring; treatments at rightage (“optimal” age)Benefits Better vaccines Vaccines made of DNA/RNA existingvaccines in our bodies without risks Activation of the immune system without causinginfections Inexpensive, stable, easy to store and engineer Improvements in drug discovery Using genome targets more easily discoverpotential therapies Previously failed drug candidates can be revivedBenefits Improves approval process Drug approval process will be facilitated Trials are targeted for specific genetic populationgroups Greater degrees of success Cost/risk of clinical trials will be reducedbecause of the individual-target basis Decreases overall cost of health care Decreases in ADR, failed drug trials, time to getdrug approval, medication times, number of trialmedications, effects of disease on body Increase in range of possible drug targetsIssues Still a complicated method of finding theSNPs that affect a specific drug response Limited drug alternatives Disincentives for drug companies for makemultiple pharmacogenomic products Educating healthcare providers Economic issues Ethical issuesNow Future Current: Researchers are now trying to catalog as many geneticvariances (SNPs) in the human genome as possible DNA must be sequenced for presence of SNPs Problem: traditional gene sequencing technology = slowand expensive Future: DNA microarrays (DNA chips) can make it possible fordoctors to examine patients for specific SNPs quickly andaffordably Takes only a couple of hours to screen 100,000 SNPs SNP screening in the doctor’s office to determine drugresponse prior to drug
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