pharmacogenomics by rajesh .I

WELCOME

PHARMACOGENOMICS A promise of personalized medicine

Seminar on

UNDER GUIDENCE OF Mrs. M sandhya M.pharm Assistant professor

CONTENTS Introduction Definition Gene index Need for pharmacogenomics Expression studies Recent research promise Single nucleotide polymorphism Pharmacogenomics in drug development Challenges posed by pharmacogenomics Scientific hurdles Positional cloning Polymorphism Enzyme polymorphism Success so far Benefits Conclusion

DEFINITION Pharmacogenomics refers to the use of DNA-based genotyping in order to target pharmaceutical agents to specific patient population in the design of drugs.

GENE INDEX

International human genome sequencing confortium created an initial index.

15,000 known genes – 17,000 gene prediction.

Function and regulation of approximately 30,000 human genes are still to be known

NEED FOR PHARMACOGENOMICS

To know the effect of polymorphism of genes for the enzymes. E.g.: cytochrome p450.

They represent the advent personalized medicine.

Treatment according to his genotype.

Increase the safety and efficiency of drug.

Individualize the drug therapy.

EXPRESSION STUDIES

Will be required to complement genomic information.

DNA array technology allows the expression monitoring of thousand of genes.

High density chip allowing analysis of virtual transcript produced by a cell.

RECENT RESEARCH PROMISES

Various technologies have been integrated to develop personalized therapy.

1. For drug resistance in HIV 2. Personalized therapy for cancer 3. Cardiovascular therapy 4. Anti depressant therapy 5. Anti hypertensive therapy

PHARMACOGENOMICS IN DRUG DEVELOPMENT

Enhance the drug discovery and development by two ways: 1. By identification of drug target. 2. By subpopulation specific drug development.

Target identification:- Genes can be used to identify new targets through the discovery of genes that are under or over expressed in cancer cells that are sensitive to anti cancer agents.

Products of such over expressed genes represents targets for inhibitors.

To ascertain the effect of chemotherapy, how cell respond to single or multiple drug therapy.

Subpopulation specific drug development:-

To identify genetic polymorphism that predispose patients to adverse drug effects.

Which occurs only in a small subset of population treated with new drug

One approach is to obtain genomic DNA before patient entered in large phase III clinical trials to search for polymorphism to avoid toxicity

CHALLENGES POSED BY PHARMACOGENOMICS

To obtain many new disease related genes and provide an explosion of new targets.

Lead to patient stratification and these new targets and as well as existing targets will be divided into subsets.To identify 5000-10,000 new potential targets because the current amount of targets is approximately 503.

SCIENTIFIC HURDLES Post genomic science guarantees a ten fold increase in the no. of targets but target validation bottle necks must be removed. Second the transcription analysis technique are not standardized and the studies of thereproducibility limits the generalizationof conclusion drawn.Thirdly multiple differences are normally observed & isolation of several transcribed sequences is not an easy task.

SINGLE NUCLEOTIDE POLYMORPHISMSingle point mutation – change protein structure.

Responsible for many diseases.

SNP’s changes – Receptors Transfer proteins Drug metabolizing enzymes

Thousands of polymorphism selected as markers.

For discovery and susceptible genes.

POSITIONAL CLONINGStep 1 It involves isolation of genes. And phenotype expression of a mutation of these genes resulting in particular diseased state. Uses:- DNA finger printing. Inherited polymorphism is tracedStep 2 Identify the function of proteins expressed by the DNA. Sequence comparision with known proteins using computer data base.

POLYMORPHISM

Difference in drug effect varies.E.g.: 2 genetic variance of ACE Insertion (I-form) or deletion (D-form) of base pairs at position (278) in gene.Expression:- D-form expresses ACE highly. I-form expresses ACE lower than D-form. Which are expressed in causasien population have high risk of MS and response better to ACE inhibitors.

ENZYME POLYMORPHISM cytochrome p450:-CYP 3A- Oxidation biotransformation of 50% of therapeutic agents.Due to genetic factors 5-2 fold interindividual variability in clearence.CYP 2D6-HydroxylaseInactive in 6% of Caucasian population.CYP2CI9-Single base pair point mutation in exon5.poor metabolismgene index.

SUCCESS SO FAR

Colorectal cancer:- Second most common cause of cancer in Europe and USA. 5 fluoro- uracil based chemotherapy first line treatment is very poor. Combination with irinotican is effective but produces adverse effects. Polymorphism in enzyme system is identified by pharmacogenomic studies.

Non small cell lung cancer:-

Pharmacogenomic approach has a potential to great improvement in survival of subpopulation of patients. To over come the resistance to drug is one of many challenge of current cancer. To identify patients more likely benefits to identify which chemotherapy regimen to use. DNA micro array but gene expression of different cancer in human. Optimization of cancer chemotherapy.

Cardiovascular therapy:-

In management of hypertension.

Identification of genetic markers of drug response for better control of blood pressure.

Identification of polymorphism in blood pressure by receptors RAAS,ADBR.

Coronary artery diseases:-

Statins: First line of drugs in case of CAD

Pharmacogenomics have great impact on statin therapy.

Pathophysiological mechanism of adverse effects as a result are identified.

Warfarin: Narrow therapeutic index.

Inter individual variability is ten fold to obtain therapeutic response.

Low dose- no effect.

High dose- rise of over bleeding.

Genetic variation in cytochrome enzymes influence warfarin doses.

BENEFITS Exclude those people who are known to have negative response to drug. Increase the probability that the drug might be success with particular population. Pre screening clinical trails also helps in reducing drug cost by Smaller Faster More inexpensive clinical trails Ability to access an individual reactions to a drug before prescribing.

CONCLUSION

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