[RSC Drug Discovery] Human-based Systems for Translational Research || Contents

  • View
    213

  • Download
    0

Embed Size (px)

Text of [RSC Drug Discovery] Human-based Systems for Translational Research || Contents

  • Dow

    nloa

    ded

    on 0

    8/12

    /201

    4 17

    :09:

    19.

    Publ

    ishe

    d on

    08

    Dec

    embe

    r 20

    14 o

    n ht

    tp://

    pubs

    .rsc

    .org

    | do

    i:10.

    1039

    /978

    1782

    6201

    36-F

    P011ContentsChapter 1RSC Drug DiscoHuman-based SEdited by Rober The Royal SocPublished by thAccess to Human Cells and Tissues 1

    Gerry Thomas1.1very Seystemst Colemiety ofe RoyaEthics and Law Regarding Collection of HumanSamples 1

    1.1.1ries No. 4for TrananChemistl Society oThe Four Cornerstones of Ethics andBiological Samples 11.1.2 Legal Issues 2

    1.2 Practical Issues Regarding Human Tissue

    Collection and Annotation 8

    1.2.1 Obtaining Tissue with Consent for Research 9

    1.2.2 Accessing Material from a Diagnostic

    Archive 11

    1.3 Improving Access and Annotation 121.3.1 Access Policies 12

    1.3.2 Annotation 131.4 Summary 14

    References 14Chapter 2 Functional Studies with Human Isolated Tissues to BetterPredict Clinical Safety and Efficacy 17

    David C. Bunton2.1 Introduction 17

    2.2 Sourcing, Storing and Transporting Human Fresh

    Tissues: The First Step is the Most Important 211slational Research

    ry 2015f Chemistry, www.rsc.org

    xi

  • xii Contents

    Dow

    nloa

    ded

    on 0

    8/12

    /201

    4 17

    :09:

    19.

    Publ

    ishe

    d on

    08

    Dec

    embe

    r 20

    14 o

    n ht

    tp://

    pubs

    .rsc

    .org

    | do

    i:10.

    1039

    /978

    1782

    6201

    36-F

    P011

    View Online2.3 Common Experimental Approaches toInvestigations in Isolated Fresh Human Tissues 23

    2.3.1 Tissue Baths and Wire Myographs 23

    2.3.2 Perfusion Myographs 25

    2.3.3 Organoculture Systems and Precision-Cut

    Tissue Slices 25

    2.3.4 Membrane Transport and Ussing Chambers:

    Skin, Lung Mucosa, Gastrointestinal Tractand Glandular Tissues 282.4 Applications of Functional Tissues in DrugDevelopment: Safety, Efficacy and PersonalisedMedicines 29

    2.4.1 Predicting Efficacy in Clinically Relevant

    Human Tissues 30

    2.4.2 Predicting Safety and Toxicology Risks Using

    Functional Tissues 31

    2.4.3 Functional Tissues and the Development of

    Personalised Medicines 32

    2.5 Summary 35Acknowledgements 35

    References 35Chapter 3 Translational Research in Pharmacology and ToxicologyUsing Precision-Cut Tissue Slices 38

    G. M. M. Groothuis, A. Casini, H. Meurs, and P. Olinga3.1 Introduction 38

    3.1.1 Precision-Cut Tissue Slices 38

    3.1.2 Availability of Different Sources of Human

    Organs and Tissues 40

    3.1.3 Techniques to Prepare and Incubate

    Precision-Cut Tissue Slices from VariousOrgans and Tissues 413.2 Human Precision-Cut Tissue Slices in ADME andToxicology 433.3 Application of Human Precision-Cut Tissue Slices inDisease Models 47

    3.3.1 Fibrosis in Liver and Intestine 47

    3.3.2 Obstructive Lung Diseases 50

    3.3.3 Cancer Research 54

    3.3.4 Viral Infection Research 573.4 Concluding Remarks 58

    References 58

    http://dx.doi.org/10.1039/9781782620136-fp011

  • Contents xiii

    Dow

    nloa

    ded

    on 0

    8/12

    /201

    4 17

    :09:

    19.

    Publ

    ishe

    d on

    08

    Dec

    embe

    r 20

    14 o

    n ht

    tp://

    pubs

    .rsc

    .org

    | do

    i:10.

    1039

    /978

    1782

    6201

    36-F

    P011

    View OnlineChapter 4 Modelling the Human Respiratory System: Approachesfor in Vitro Safety Testing and Drug Discovery 66

    Human-Derived Lung Models; The Future of ToxicologySafety Assessment

    Zoe Prytherch and Kelly BeruBe4.1 Introduction 66

    4.1.1 Overview of the Respiratory System 66

    4.1.2 Inhalation Toxicology 67

    4.1.3 Status Quo in Safety Assessment 68

    4.1.4 In Vitro Toxicology 68

    4.1.5 Trends and Technology Uptake 694.2 Current Human-Based Models of the RespiratorySystem: An Overview 70

    4.2.1 Cells and Tissues 70

    4.2.2 General Culture Conditions 764.3 Discussion 80

    References 81Chapter 5 Complex Primary Human Cell Systems for Drug Discovery 88

    Ellen L. Berg and Alison O'Mahony5.1 Introduction 88

    5.1.1 Challenges of Target-Based Drug Discovery 88

    5.1.2 Kinase Inhibitors An Example Target Class 89

    5.1.3 Complex Primary Human Cell Systems for

    Translational Biology 90

    5.2 Case Studies Anti-Inammatory Kinase Inhibitors 955.2.1 JAK Kinase Inhibitors 95

    5.2.2 SYK Kinase Inhibitors 1015.3 Conclusions 105

    Acknowledgements 106

    References 106Chapter 6 Human in Vitro ADMET and Prediction of HumanPharmacokinetics and Toxicity Liabilities at theDiscovery Stage 110

    Katya Tsaioun6.1 Introduction 110

    6.2 The Science of ADMET 112

    6.3 The ADMET Optimisation Loop 113

    6.4 Impact of Early Human Pharmacokinetics

    Prediction 116

    http://dx.doi.org/10.1039/9781782620136-fp011

  • xiv Contents

    Dow

    nloa

    ded

    on 0

    8/12

    /201

    4 17

    :09:

    19.

    Publ

    ishe

    d on

    08

    Dec

    embe

    r 20

    14 o

    n ht

    tp://

    pubs

    .rsc

    .org

    | do

    i:10.

    1039

    /978

    1782

    6201

    36-F

    P011

    View Online6.5 New Human ADMET Prediction Tools 117

    6.5.1 The Blood-Brain Barrier Challenge 117

    6.5.2 Mechanisms of Human Toxicity 121

    6.5.3 The Power of Multiparametric Screening

    in Toxicology 125

    6.6 Bridging the Gap between in Vitro and in Vivo 126

    6.7 Conclusions and Future Directions 128References 129Chapter 7 Body-on-a-Chip Technology and SupportingMicrouidics 132

    A. S. T. Smith, C. J. Long, C. McAleer, X. Guo, M. Esch,J. M. Prot, M. L. Shuler, and J. J. Hickman7.1 Introduction 132

    7.2 Multi-Organ in Vitro Models 133

    7.3 Functional Single-Organ in Vitro Models 1367.3.1 Heart/Cardiac Tissue 137

    7.3.2 Lung 137

    7.3.3 Gastrointestinal (GI) Tract 139

    7.3.4 Liver 141

    7.3.5 Kidney 143

    7.3.6 Adipose Tissue 143

    7.3.7 Central Nervous System (CNS)/Peripheral

    Nervous System (PNS) 144

    7.3.8 Skeletal Muscle 150

    7.3.9 Blood Surrogate 1507.4 Microuidics 151

    7.5 Concluding Remarks 153Acknowledgements 153

    References 153Chapter 8 Utility of Human Stem Cells for Drug Discovery 162

    Satyan Chintawar, Martin Graf, and Zameel Cader8.1 Introduction 162

    8.2 Existing Approaches to Drug Discovery 164

    8.3 Advances in Human Stem Cell Technology 1658.3.1 Embryonic Stem Cells 165

    8.3.2 Reprogramming Somatic Cells 1668.4 iPSC-Based Disease Models 167

    8.4.1 iPSC-Based Neurological and Psychiatric

    Disease Models 167

    8.4.2 iPSC-Based Cardiovascular Disease Models 169

    8.4.3 Other Examples of iPSC-Based Disease

    Models 172

    8.4.4 Genome Editing Tools 173

    http://dx.doi.org/10.1039/9781782620136-fp011

  • Contents xv

    Dow

    nloa

    ded

    on 0

    8/12

    /201

    4 17

    :09:

    19.

    Publ

    ishe

    d on

    08

    Dec

    embe

    r 20

    14 o

    n ht

    tp://

    pubs

    .rsc

    .org

    | do

    i:10.

    1039

    /978

    1782

    6201

    36-F

    P011

    View Online8.5 Use of iPSCs in Drug Efficacy Assessment 173

    8.5.1 Target-Based Screening versus Phenotypic

    Screening 173

    8.5.2 Examples of Drug Testing to Validate iPSC-

    Based Models 175

    8.5.3 Drug Screens on iPSC-Based Models 1768.6 Toxicity Testing Using iPSC-Based Models 177

    8.6.1 Cardiotoxicity 177

    8.6.2 Hepatotoxicity 178

    8.6.3 Neurotoxicity 1788.7 Integration of iPSCs in Drug Discovery 179

    8.7.1 Challenges 179

    8.7.2 Future Directions 1808.8 Emerging Resources of Diseased iPS Cell Lines 181

    8.8.1 StemBANCC (Stem Cells for Biological

    Assays of Novel Drugs and PredictiveToxicology) 1818.8.2 EBiSC (European Bank for InducedPluripotent Stem Cells) 1828.8.3 HipSci (Human Induced Pluripotent StemCells Initiative) 1838.9 Summary 183

    References 183Chapter 9 In Silico Solutions for Predicting Efficacy and Toxicity 194

    Glenn J. Myatt and Kevin P. Cross9.1 Introduction 194

    9.2 Representing Chemical Structures and

    Associated Data 196

    9.2.1 Overview 196

    9.2.2 Chemical Representation 196

    9.2.3 Biological Data Representation 199

    9.2.4 Calculated Data 1999.3 Searching Chemical Databases 199

    9.4 Calculating Molecular Fragment Descriptors 2019.4.1 Overview of Fragment Types 201

    9.4.2 Predened Features 202

    9.4.3 Structural Alerts 203

    9.4.4 Common Chemical Scaffolds 204

    9.4.5 Scaffolds Associated with Data 2049.5 Understanding StructureActivity or ToxicityRelationships 205

    9.5.1 Overview 205

    9.5.2 Classication Based on Substructures 205

    http://dx.doi.org/10.1039/9781782620136-fp011

  • xvi Contents

    Dow

    nloa

    ded

    on 0

    8/12

    /201

    4 17

    :09:

    19.

    Publ

    ishe

    d on

    08

    Dec

    embe

    r 20

    14 o

    n ht

    tp://

    pubs

    .rsc

    .org

    | do

    i:10.

    1039

    /978

    1782

    6201

    36-F

    P011

    View Online9.5.3 Clustering 205

    9.5.4 Decision Trees 2079.6 Quantitative StructureActivity Relationship (QSAR)Modelling 208

    9.6.1 Overview 208

    9.6.2 Building Models 208

    9.6.3 Applying Models 210

    9.6.4 Model Validation 211

    9.6.5 Explaining the Results 2119.7 Regulatory in Silico Case Study 212

    9.8 Prediction of Huma