PHARMACOGENOMICS By V.VYTHESHWARAN

Problems with Rx Drugs We are all different… Most of us are treated in the same way Trial and error

Implications Time: Trips to and from doctor Money: Thousands spent on ineffective medications Death/sickness: 2.2 million serious cases and over 100,000 deaths.

PURINE ANALOGUES 6-mercaptopurine, 6-thioguanine, azathioprine Used to treat lymphoblastic leukemia, autoimmune disease, inflammatory bowel disease and after transplant. Interfere with nucleic acid synthesis Therapeutic index limited by myelosuppression

Metabolism of 6-Mercaptopurine Levels of Thiopurine s- methyl transferase (TPMT) can drastically affect levels of thioguanines More TPMT = less thioguanines. Associated with risk of severe marrow toxicity Shows considerable variability in population

Variations in TPMT Genes

6-MP and TPMT Story Summary Clinical variability (toxicity). Cellular variability (TPMT activity, thioguanine nucleotides concentrations). Genetic variability (genome variations in TPMT gene) How can we support this type of discovery using informatics?

AN ANSWER???? Pharmacogenomics : The study of how an individuals genetic inheritance affects the body’s response to drugs.

DEFINITION Pharmacogenomics refers to the identification and elucidation of genetic variations that will impact the efficacy of drugs or offer different targets. Rather than being a radically new approach to medicine, pharmacogenomics essentially applies concepts about variations in drug metabolism to the rest of genome. Pharmacogenomics refers to the application of tools from the functional genomics toolbox to the discipline of pharmacogenetics.

BACKGROUND Fundamental to pharmacogenomics is the identification and mapping of the most common form of genetic variation - known as single nucleotide polymorphisms (SNPs). SNPs occur on average every 1000 nucleotides. Due to their relatively high density (compared with other forms of genetic variation), SNPs can serve as useful markers to navigate through the genome, whether one is trying to locate disease-linked genes or to determine the risk of developing a disease. Of the estimated total of 30 million SNPs in the entire genome, a few hundred thousand are thought to occur within these regions and of these perhaps only a few thousand account for disease outcomes.

HISTORY The genetic contribution to drug metabolism was originally defined using variations in drug levels or responses of individuals and families. This was suggested on a theoretical basis by Motulsky in The word "pharmacogenetics" was coined approximately forty years ago by Vogel in Kalow wrote the first text book on this subject in The field of pharmacogenetics was further stimulated in the late 1970s when Vesell et al. demonstrated that identical twins were more similar than fraternal twins in regard to the plasma half-lives of therapeutically used drugs.

PROSPECTS Pharmaceutical development and therapeutic strategies in the coming years. Safer, more effective drugs. Better diagnostics, and improved clinical trials, it may even lead to an era of "personalized medicine" where therapies are tailored to the genetic makeup of different populations.

THE NEED… AN ILLUSTRATION A drug called azathioprine, is used in autoimmune disorders, and childhood leukemia is metabolized, by the enzyme called TMPT. Less than 0.5 % of Caucasians carry a gene variant on both chromosomes that produces an inactive protein and so can not metabolize the drug. When patients with that gene variant are treated with azathioprine, its blood levels built up to toxic levels, leading to acute bone marrow failure. This happened to a boy who was started on the drug and had to be rushed to the Mayo Clinic for a marrow transplant, which saved his life. A pharmacogenomic genetic test has been developed to identify patients with this deficiency which permits the use of an alternative therapy.

OBTAINING THE DNA Person’s DNA sequenced through micro array techniques Micro arrays- evolving technology to examine patients for specific SNPs quickly and affordably One micro array screen 100,000 SNPs in a few hours As technology develops, SNP screening commonplace

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. Anticipated benefits of Pharmacogenomics

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

Advent of better, Safer Drugs 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. Anticipated benefits of pharmacogenomics

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. Anticipated benefits of pharmacogenomics

Improvements in the Drug Discovery and Approval Process –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. –Drug approval process – facilitated as trials are targeted for specific genetic population groups --providing greater degrees of success. –Cost and risk of clinical trials will be reduced by targeting only those persons capable of responding to a drug. –As reported in the April 2001 issue of Pharmaceutical Executive, "By 2010, pharmacogenomics is expected to cut the cost of R&D by $33 million per product!!!” Anticipated benefits of pharmacogenomics

Decrease in the Overall Cost of Health Care –Number of adverse drug reactions. –Number of failed drug trials, & the time it takes to get a drug approved. –Time period for which the patients are on medication. –Number of medications patients must take to find an effective therapy. –Effects of a disease on the body (through early detection). –Increase in the range of possible drug targets. Anticipated benefits of pharmacogenomics

THE NEEDS Softwares Pharmacogenomic tests New drugs based on pharmacogenomic information Secure genotype banks Web- based clinical trials

THE BIG ? Can these studies actually be done for enough diseases? Will enough diseases have a stronger genetic than environmental component? Will SNPs be generally useful to find genetic associations?

Risk of pharmacogenomics

Issues Raised by Ethics Committees Patient confidentiality/data privacy Specify genes Scope of sample use for future research Length of storage period Disclosure of individual results to patients Limited sample withdrawal period Samples cannot be used for commercial purpose Sample ownership Investigator role in access/use of samples/data

”CONSUMER GENOMICS" Major pharmaceutical companies now routinely study genetic effects on drug metabolism and response as part of drug discovery and development. Genetic variation has been shown to affect the action of many of the most important drugs in the pharmacopia. A new field of "consumer genomics" has been spawned to bring these discoveries directly to the public.

Fairness in the use of genetic information by insurers, employers, courts, schools, adoption agencies, and the military, among others. –Who should have access to personal genetic information, and how will it be used? Privacy and confidentiality of genetic information. – Who owns and controls genetic information? Psychological impact and stigmatization due to an individual's genetic differences. –How does personal genetic information affect an individual and society's perceptions of that individual? Ethical, Legal and Social Implications

Reproductive issues including adequate informed consent for complex and potentially controversial procedures, use of genetic information in reproductive decision making, and reproductive rights. –Do healthcare personnel properly counsel parents about the risks and limitations of genetic technology? How reliable and useful is fetal genetic testing? Ethical, Legal and Social Implications

Uncertainties associated with gene tests for susceptibilities and complex conditions (e.g., heart disease) linked to multiple genes and gene-environment interactions. –Should testing be performed when no treatment is available? Should parents have the right to have their minor children tested for adult-onset diseases? Are genetic tests reliable and interpretable by the medical community? Ethical, Legal and Social Implications

Conceptual and philosophical implications regarding human responsibility, free will vs genetic determinism, and concepts of health and disease. –Do people's genes make them behave in a particular way? Can people always control their behavior? What is considered acceptable diversity

Safety and environmental issues concerning genetically altered foods and microbes Commercialization of products including property rights (patents, copyrights, and trade secrets) and accessibility of data and materials –Who owns genes and other pieces of DNA? Ethical, Legal and Social Implications

THE FUTURE????

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