Assignment – 01Pharmacogentics-Genomics in

relation to molecular Diagnosis -Molecular Therapeutic technologies

By

Narra Naga Pavan Kumar (KVPY Fellow)

1st M.Tech Biotech (14IS1D0301)

Institute of Science & Technology, JNTUK University

Interrelation between the pharmacogenomics and Genetics• Both are nearly same but the study range is variying

• Pharmacogenomics is the branch of pharmacology that involves the study of drug response with the entire compliment of genes.

• Pharmacogenetics, refers to study of drug response with a relatively restricted number of genes.

Pharmacogenomics - Genetics

• genome-wide approaches

• more than 1,000,000 polymorphisms

• Study of polymorphisms

• Example :- next generation Sequenceing

• Gene wide approach

• More then 25, 000 genes

• Study of mutations

• Example :- Microarrays

Why the study is needed

• Due the genomic variation

• Due to the environmental factors - Ecogenetics

• Example :- ethanol sensitivity, which is related to acetaldehyde-dehydrogenase deficiency.

• Due the food we are taking

• Example :- milk intolerance because of lactase deficiency.

• The immune responses of a person

• Toxicogenetics :- Example :- carcinogens

•Results = personalised medicine

Molecular Therapeutic technologies

Personalised medicine

• Personalized medicine is a broad health care that is informed by each person’s unique clinical, genetic, genomic, and environmental information to individualizing patient care across the continuum (from health to disease).

• Goal :- to optimize medical care and outcomes for each individual, to include treatments, medication types and dosages, and/or prevention strategies may differ from person to person

Therapeutic principles• All drug effects vary from person to person and all drug effects are influenced by

genes.

• Most drug responses are multifactorial (that is, many genes and manyenvironmental factors contribute to them).

• Genetic polymorphisms of single genes, including mutations in coding sequences,gene duplications, gene deletions and regulatory mutations affect numerous drug-metabolizing enzymes. Several cytochrome-P450 enzymes (for example, CYP2D6and CYP2C9), N-acetyltransferases (NAT2), thiopurine methyltransferase (TPMT)and UDPglucuronosyltransferases (UDP-GT) are examples. Individuals that possessthese polymorphisms are at risk of experiencing documented adverse reactions orinefficacy of drugs at usual doses.

• Genetic polymorphisms of drug targets and drug transporters are increasinglyrecognized (receptors, ion channels, growth factors) as causing variation in drugresponses.

• Several targets of cancer therapy, for example, the epidermal-growth-factorreceptor, respond to treatment only in subgroups of patients who carry sensitizingmutations of these targets.

• The frequency of variation of drug effects,whether multifactorial or genetic,varies considerably in ethnically defined populations (for example, alleles of N-acetyltransferases).

• Application of response-predictive genetic profiles (for example, genotyping forpolymorphisms in antidepressant or cancer-drug therapy) on clinical outcomeshas, so far, been done mostly in academic centres and has not yet reached clinicalpractice.

The main principle involved is

Genetic Polymorphisms in Drug Metabolism and Disposition• Genetic Polymorphisms in Drug Targets

• Genetic Polymorphisms in Drug Transporters

Example :- selection and dosing of chemotherapyfor a patient with acute lymphoblastic leukemia(ALL)• Genetic polymorphisms in drug-metabolizing enzymes can have a profound effect

on toxicity and efficacy of medications used to treat ALL and that individualizing drug dosages can improve clinical outcome.

• It has also been established that the genotype of leukemic lymphoblasts is an important prognostic variable that can be used to guide the intensity of treatment.

• all these will be placed on a chip called ALL Chip give the results for a selective therapy. (reference William E. Evans, et al Science 286, 487, 1999) as same as microarray technology.

Examples for the drug metabolism

Molecular Diagnosis

Diagnosis

• Next generation sequencing.

• DNA chip.

• Transcriptome profiling.

References:-• Genomic and personalized medicine: foundations and applications GEOFFREY S.

GINSBURG et al., Translational Research December 2009;272 – 287.

• Molecular Genetic Markers as A Basis for Personalized Medicine Sonja Pavlovi et al., J Med Biochem 33: 8–21, 2014.

• Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment Jürgen Brockmöller et al., Eur J Clin Pharmacol (2008) 64:133–157.

• Pharmacogenomics: Translating Functional Genomics into Rational TherapeuticsWilliam E. Evans, et al. Science 286, 487 (1999).

• Pharmacogenetics – five decades of therapeutic lessons from genetic diversity, Urs A.Meyer, Nature Reviews Genetics September 2004, vol 4, 669 -676