15. STEPS INVOLVED IN THE GENETIC REVOLUTION IN MEDICINE Disease with genetic component Map Clone gene Gene therapy Time Accelerated by Human Genome Project Diagnostics Preventive Medicine Pharmacogenomics Understand basic biologic defect Drug therapy

16. STEPS INVOLVED IN THE GENETIC REVOLUTION IN MEDICINE Uncovering the genetic contributions to an illness is accomplished by cloning the gene for the disease, with the use of the tools of the Human Genome Project. Once the contributing genes and their disease - predisposing variants have been identified, diagnostic tests can be developed to predict future risk - but these tests are most effective when a preventative strategy is available to reduce the risk in persons found to be predisposed to a particular disease. Another rapidly developing application of diagnostics is pharmacogenomics, the prediction of responsiveness to drugs. Ultimately, the real payoff of genetic research will be the development of new gene therapies and drug therapies, but they will generally require more years of intensive research.

17. Traditional medical uses of natural products DRUG DISCOVERY SOURCES IN CONTEXT Sources of compounds Chemical libraries Historical compound collections Natural product libraries Combinatorial libraries Therapeutic Targets Rational synthesis Antisense oligonucleotides Drug discovery screening assays Lead optimisation and candidate selection Empirical understanding of physiology and pathology Molecular cloining of receptors and signalling molecules Genomics Drug development

18. DRUG DISCOVERY SOURCES IN CONTEXT Different types of chemical compounds (top left hand side of diagram) are tested against bioassays that are relevant to therapeutic targets, which are derived from several possible sources of information (right hand side). The initial lead compounds discovered by the screening process are optimised by analogue synthesis and tested for appropriate pharmacokinetic properties. The candidate compounds then enter the development process, involving regulatory toxicology studies and clinical trials.

27. Unmet Medical Need COMMERCIAL CONSIDERATIONS Examples: 1. Cystic fibrosis 2. 3. Heart failure many cancers 4. Allergic Rhinitis     IMPACT

33. STAGES OF DEVELOPMENT Clinical Development Nos. of subject Phase Activities 10’s-100’s 10’s 1 2 a Safety & tolerability kinetics H.N.V & Dynamics Dose response Proof of concept Early patient studies: Proof of concept “Powered” studies for efficacy b

34. SILDENAFIL (Viagra) PDE5 GTP GDP Nitric Oxide Sildenafil Guanylate Cyclase Cavernosal smooth muscle Relaxation Penile Erection GMP + -

41. Examples: (1) High penetrant changes in single genes - Haemochromatosis - Phenylketonuria - Familial hypercholesterolaemia (2) Environmental interplay and multiple genes - Highly heritable subgroups e.g. (1) B RCA 1 & 2 in breast cancer (2) HNF - 4  in MODY type I (3) GCK in MODY type II DIAGNOSTIC APPLICATIONS FROM GENETICS

43. DNA TECHNOLOGY AND MICRO-ARRAY SYSTEMS (2) Examples: (1) Alzheimer patients with E4 subtype of gene for apolipoprotein E (APO E 4) affecting cholinergic brain function less likely to respond to tacrine (2) CETP (cholesteryl ester transfer protein) important in control of HDL metabolism

44. DNA CHIP AND MICRO-ARRAY TECHNOLOGY (2) Stage Time (Years) Major Activity Research Clinical Research Registration Marketing 2-7 2-4 1-2 Candidate Compound Plausible - Hypothesia Confirmation of dose range. Explorative - treatment. Safety database Preparation of Dossier