Personalized Medicine - scientific and commercial aspects |
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0. Executive Summary ................. 16 1. Basic Aspects...... 18 Definition of personalized medicine 18 Historical evolution of medical concepts .............. 19 Molecular biological basis of personalized medicine ................ 21 The human genome....21 Chromosomes............22 Genes.22 The genetic code...22 Gene expression ...22 DNA sequences and structure .....23 Single nucleotide polymorphisms 23 Genotype and haplotypes...........24 Non-SNP genetic variations .............24 Insertions and deletions in the human genome ..24 Large scale variation in human genome ............25 Variation in copy number in the human genome.25 Structural variations in human genome.............26 Basics technologies for developing personalized medicine ...... 26 Definitions of technologies relevant to personalized medicine........26 Problems with the ICH definitions of pharmacogenomcis and pharmacogenetics...27 Relationship of various technologies to personalized medicine.......27 Conventional medicine versus personalized medicine.............. 28 Role of genetics in future approaches to healthcare ................ 29 Genetic medicine........29 Human disease and genes...............29 Mass analysis of DNA from whole populations .........30 Role of genetics in development of personalized medicines...........30 Genetic databases.30 Genetic epidemiology.................31 Limitations of medical genetics and future prospects ..............31 Genetics vs. epigenetics.............32 Role of systems biology in personalized medicine 32 A personalized approach to environmental factors in disease.. 32 Reclassification of diseases............. 33 2. Molecular Diagnostics in Personalized Medicine ............... 36 Introduction............... 36 Molecular diagnostic technologies .. 36 Direct dideoxy DNA sequencing (DDS)...................37 Single-stranded conformation polymorphism (SSCP) analysis .......37 Heteroduplex analysis (HA) .............37 The WAVE System......38 DirectLinear™ Analysis38 Denaturing high-performance liquid chromatography (DHPLC)......38 Denaturing Gradient Gel electrophoresis (DGGE).....38 Chemical cleavage mismatch (CCM) .39 Multiplex Allele-Specific Diagnostic Assay ...............39 Representational oligonucleotide microarray analysis...................39 Cleavase Fragment Length Polymorphism (CFLP) ....39 Restriction fragment length polymorphism (RFLP) ...39 Arrayed primer extension (APEX) .....40 Enzymatic Mutation Detection (EMD) 40 T cells and molecular diagnosis ........40 The chorioallantoic membrane assay 41 Sequencing ...............41 Multiplex DNA sequencing ..........41 Sequencing in microfabricated high-density picoliter reactors ..42 Nanopore-based sequencing .......42 Electrophoresis in nanochannels..42 Whole genome sequencing ..............42 Biochips and microarrays................ 43 Application of biochip technology in developing personalized medicine ................43 Standardizing the microarrays .........45 Biochip technologies ...45 GeneChip .............45 - 4 - AmpliChip CYP450 .45 Microfluidics ..............47 Lab-on-a-chip .......48 Micronics' microfluidic technology48 LabCD..................48 Microfluidic automated DNA analysis using PCR..48 Integrated microfluidic bioassay chip ................49 Electronic detection of nucleic acids on microarrays .49 Strand displacement amplification on a biochip .......49 Rolling circle amplification on DNA microarrays .......50 Universal DNA microarray combining PCR and ligase detection reaction ..............50 Protein biochips .........50 ProteinChip...........51 LabChip for protein analysis........51 TRINECTIN proteome chip..........52 Protein expression microarrays ...52 Microfluidic devices for proteomics-based diagnostics .............53 New developments in protein chips...................53 Protein chips for personalized medicine.............54 SNP genotyping .......... 54 Haplotyping..............55 Haplotype Specific Extraction......55 Computation of haplotypes.........56 HapMap project.....56 Predictingdrug response with HapMap...............57 Companies developing haplotyping technology...57 Technologies for SNP analysis..........57 Biochip and microarray-based detection of SNPs .....58 SNP genotyping by MassARRAY...58 Biochip combining BeadArray and ZipCode technologies..........59 SNP-IT primer-extension technology.................59 OmniScan SNP genotyping .........60 Affymetrix Variation Detection Arrays ...............60 Use of NanoChip for detection of SNPs ..............60 DNA sequencing.........60 Electrochemical DNA probes ............61 Single base extension-tag array .......61 Laboratory Multiple Analyte Profile ...61 PCR-CTPP (confronting two-pair primers) ...............62 SNP genotyping on a genome-wide amplified DOP-PCR template...62 TaqMan real-time PCR 62 Non-Enzymatic Amplification Technology................63 SNP genotyping with gold nanoparticle probes ........63 Locked nucleic acid.....63 Molecular inversion probe based assays .................64 Pyrosequencing..........64 Reversed enzyme activity DNA interrogation test ....65 Smart amplification process version 265 Zinc finger proteins ....65 UCAN method (Takara Biomedical)...66 Mitochondrial SNPs.....66 Limitations of SNP in genetic testing.66 Concluding remarks on SNP genotyping .................67 Companies involved in developing technologies/products for SNP analysis...........67 Impact of SNPs on personalized medicine...............68 Optical Mapping .......... 69 Role of nanobiotechnology in molecular diagnostics................ 69 Cantilevers for personalized medical diagnostics .....70 Nanopore-based technology for single molecule identification .......70 Role of biomarkers in personalized medicine ....... 71 Biomarkers for diagnostics ..............71 Biomarkers for drug development ....72 Application of proteomics in molecular diagnosis 72 Proteomic strategies for biomarker identification .....72 Proteomic technologies for detection of biomarkers in body fluids..................73 Protein patterns .........73 Layered Gene Scanning ..................73 Comparison of proteomic and genomic approaches in personalized medicine .......74 Gene expression profiling ............... 74 DNA microarrays........75 Analysis of single-cell gene expression...................76 - 5 - Gene expression profiling based on alternative RNA splicing .........76 Whole genome expression array ......77 Tangerine™ expression profiling.......77 Gene expression analysis on biopsy samples ..........78 Serial analysis of gene expression (SAGE)..............78 Multiplexed Molecular Profiling .........79 Gene expression analysis using competitive PCR and MALDI TOF MS ..................79 Monitoring in vivo gene expression by magnetic resonance imaging ...................79 Companies involved in gene expression analysis .....80 Monitoring in vivo gene expression by molecular imaging ....... 81 Molecular imaging and personalized medicine ..... 81 Glycomics-based diagnostics .......... 81 Combination of diagnostics and therapeutics....... 82 Companies combining diagnostics and therapeutics.82 Point-of-care diagnosis................... 84 Companies developing point-of-care diagnostic technologies ........85 Point-of-care diagnosis of infections .87 Advantages versus disadvantages of point-of-care diagnosis ........87 Future prospects of point-of-care diagnosis ............88 Role of diagnostics in integrated healthcare ........ 88 Concept of integrated healthcare......88 Components of integrated healthcare 89 Screening.............89 Disease prediction .89 Early diagnosis......90 Prevention............90 Therapy based on molecular diagnosis ..............90 Monitoring of therapy ................90 Advantages and limitations of integrated healthcare90 Commercially available systems for integrated healthcare ............91 Future of molecular diagnostics in personalized medicine ....... 91 3. Pharmacogenetics ................... 92 Basics of pharmacogenetics ............ 92 Role of molecular diagnostics in pharmacogenetics................. 93 Role of pharmacogenetics in pharmaceutical industry ............. 94 Study of the drug metabolism and pharmacological effects...........94 Causes of variations in drug metabolism ................94 Enzymes relevant to drug metabolism ...................95 Pharmacogenetics of phase I metabolism...............95 CYP450................95 P450 CYP 2D6 inhibition by selective serotonin reuptake inhibitors ................97 Lansoprazole and cytochrome P450 ..................98 Glucose-6-phosphate dehydrogenase................98 Pharmacogenetics of phase II metabolism..............99 N-Acetyltransferase ...................99 Uridine diphosphate-glucuronosyltransferase .....99 Measurement of CYP isoforms........ 100 Polymorphism of drug transporters. 100 Genetic variation in drug targets .... 101 Polymorphisms of kinase genes. 101 Effect of genetic polymorphisms on disease response to drugs.... 102 Ethnic differences in drug metabolism.................. 102 Gender differences in pharmacogenetics .............. 103 Role of pharmacogenetics in drug safety .............. 103 Adverse drug reactions ............ 103 Role of pharmacogenetics in warfarin therapy.. 104 Role of pharmacogenetics in carbamazepine therapy ............ 105 Malignant hyperthermia ........... 105 ADRs related to toxicity of chemotherapy ........ 106 FDA consortium linking genetic biomarkers to serious adverse events.......... 106 Therapeutic drug monitoring, phenotyping, and genotyping........ 107 Therapeutic drug monitoring..... 107 Phenotyping ....... 107 Genotyping......... 109 Genotyping vs phenotyping ...... 109 Phenomics............... 110 Limitations of genotype-phenotype association studies ......... 110 Molecular toxicology in relation to personalized medicines.......... 110 Toxicogenomics .. 110 Companies involved in molecular toxicology .... 111 - 6 - Gene expression studies .......... 112 Transcriptome profiling studies . 112 Genomics and the prediction of xenobiotic toxicity................ 113 Pharmacogenetics in clinical trials .. 113 Postmarketing pharmacogenetics ... 114 Clinical implications of pharmacogenetics.......... 114 Examples of use of pharmacogenetics in clinical pharmacology ... 114 Linking pharmacogenetics with pharmacovigilance 116 Recommendations for the clinical use of pharmacogenetics ........ 116 Limitations of pharmacogenetics .. 116 Academic research in pharmacogenetics ........... 117 Future role of pharmacogenetics in personalized medicine.... 118 4. Pharmacogenomics................ 120 Introduction............. 120 Basics of pharmacogenomics ........ 120 Pharmacogenomics and drug discovery ............. 120 Preclinical prediction of drug efficacy .............. 122 Pharmacogenomics and clinical trials ................ 122 Impact of genetic profiling on clinical studies ........ 124 Limitations of the pharmacogenomic-based clinical trials............ 125 Pharmacogenomic aspects of major therapeutic areas .......... 125 Oncogenomics ......... 125 Oncogenes ......... 126 Tumor suppressor genes .......... 126 Cardiogenomics ....... 127 Neuropharmacogenomics .............. 129 Pharmacogenomics of Alzheimer's disease....... 130 Pharmacogenomics of depression................... 130 Pharmacogenomics of schizophrenia............... 131 Companies involved in neurogenomics-based drug discovery. 131 5. Role of Pharmacoproteomics . 134 Basics of proteomics . 134 Proteomic approaches to the study of pathophysiology of diseases............ 134 Single cell proteomics for personalized medicine ... 135 Diseases due to misfolding of proteins ................. 135 Therapies for protein misfolding 136 Significance of mitochondrial proteome in human disease .......... 137 Proteomic technologies for drug discovery and development 137 Role of reverse-phase protein microarray in drug discovery ........ 137 Role of proteomics in clinical drug safety.............. 137 Toxicoproteomics ..... 138 Application of pharmacoproteomics in personalized medicine 139 6. Role of Metabolomics in Personalized Medicine .............. 140 Metabolomics and metabonomics . 140 Metabolomics bridges the gap between genotype and phenotype .............. 140 Metabolomics, biomarkers and personalized medicine........... 141 Metabolomic technologies............. 141 Urinary profiling by capillary electrophoresis......... 142 Lipid profiling........... 142 Role of metabolomics in biomarker identification and pattern recognition .......... 143 Validation of biomarkers in large-scale human metabolomics studies................ 143 Pharmacometabonomics............... 143 Metabonomic technologies for toxicology studies.................. 144 Metabonomics/metabolomics and personalized nutrition...... 144 7. Personalized Biological Therapies.............. 146 Introduction............. 146 Recombinant human proteins ....... 146 Therapeutic monoclonal antibodies 146 Cell therapy............... 147 Autologous tissue and cell transplants.................. 147 Stem cells ............... 147 Role of stem cells derived from unfertilized embryos............. 147 Cloning and personalized cell therapy .................. 148 Use of stem cells for drug testing ... 148 Gene therapy ............ 148 Personalized cancer vaccines........ 149 - 7 - Patient-specific cancer vaccines ..... 149 Personalized cancer vaccines .... 149 Antigen-specific vaccines............... 150 Autologous cell vaccines................ 150 Individual cancers are antigenically distinct .......... 150 Autologous HSP70-peptide vaccine................. 151 Personalized melanoma vaccines.... 151 Antisense therapy ..... 152 RNA interference...... 152 8. Personalized Medicine in Major Therapeutic Areas ......... 154 Introduction............. 154 Management of viral infections ..... 155 Management of HIV.. 155 Differences in response of the body to HIV ...... 155 Variations in action of drugs on HIV................ 155 Role of diagnostic testing in HIV 155 CD4 counts as a guide to drug therapy for AIDS .................. 156 Drug-resistance in HIV............. 156 Measurement of Repl |
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