{"product_id":"oligonucleotidebased-drugs-and-therapeutics-preclinical-and-clinical-considerations-for-development-9781118537336","title":"OligonucleotideBased Drugs and Therapeutics","description":"\u003cb\u003eBook Synopsis\u003c\/b\u003e\u003cbr\u003eAntisense-based drugs are part of a growing number of pharmaceutical and biotech programs to treat diseases including cancer, diabetes, and ALS. Reviewing fundamentals and offering guidelines for drug discovery and development, this book is a practical guide from the safety assessment to clinical experience with antisense oligonucleotides.\u003cbr\u003e\u003cbr\u003e\u003cb\u003eTable of Contents\u003c\/b\u003e\u003cbr\u003e\u003cp\u003eList of Contributors xvii\u003c\/p\u003e \u003cp\u003ePreface xxi\u003c\/p\u003e \u003cp\u003eAcknowledgments xxii\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Mechanisms of Oligonucleotide Actions 1\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eAnnemieke Aartsma‐Rus, Aimee L. Jackson, and Arthur A. Levin\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Introduction\u003c\/p\u003e \u003cp\u003e1.2 Antisense Oligonucleotide Therapeutics 2\u003c\/p\u003e \u003cp\u003e1.2.1 Antisense Activity Mediated by RNase H 2\u003c\/p\u003e \u003cp\u003e1.2.2 The RNase H Mechanism 2\u003c\/p\u003e \u003cp\u003e1.2.3 Chemical Modifications to Enhance RNase H‐mediated Antisense Activity 3\u003c\/p\u003e \u003cp\u003e1.3 Oligonucleotides that Sterically Block Translation 5\u003c\/p\u003e \u003cp\u003e1.4 Oligonucleotides that Act Through the RNAi Pathway 5\u003c\/p\u003e \u003cp\u003e1.4.1 The RISC Pathway 5\u003c\/p\u003e \u003cp\u003e1.4.2 Mechanisms of RISC‐mediated Gene Silencing 8\u003c\/p\u003e \u003cp\u003e1.5 Chemical Modification of siRNAs and miRNAs 10\u003c\/p\u003e \u003cp\u003e1.5.1 Delivery of Therapeutic siRNAs or miRNAs 12\u003c\/p\u003e \u003cp\u003e1.6 Clinical Use of Oligonucleotides that Act through the RNAi Pathway 14\u003c\/p\u003e \u003cp\u003e1.7 Oligonucleotides that Modulate Splicing 17\u003c\/p\u003e \u003cp\u003e1.7.1 Pre‐mRNA Splicing and Disease 17\u003c\/p\u003e \u003cp\u003e1.7.2 Mechanisms of Oligonucleotide‐mediated Splicing Modulation 17\u003c\/p\u003e \u003cp\u003e1.7.3 Chemical Modifications that Enhance Activity of Oligonucleotidebased Splicing Modulators 21\u003c\/p\u003e \u003cp\u003e1.7.4 Clinical Applications of Splicing Modulators 22\u003c\/p\u003e \u003cp\u003e1.8 Conclusions 22\u003c\/p\u003e \u003cp\u003eReferences 22\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 The Medicinal Chemistry of Antisense Oligonucleotides 39\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eJonathan K. Watts\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction:The Antisense Approach and the Need for Chemical Modification 39\u003c\/p\u003e \u003cp\u003e2.1.1 How Does Medicinal Chemistry Apply to Oligonucleotides? 40\u003c\/p\u003e \u003cp\u003e2.1.2 Chemistry and Toxicity 41\u003c\/p\u003e \u003cp\u003e2.2 Why Chemically Modify an Oligonucleotide? 42\u003c\/p\u003e \u003cp\u003e2.2.1 Medicinal Chemistry Can Increase Nuclease Stability 42\u003c\/p\u003e \u003cp\u003e2.2.2 Medicinal Chemistry Can Tune Binding Affinity and Specificity 43\u003c\/p\u003e \u003cp\u003e2.2.3 Medicinal Chemistry Can Change Interactions with Cellular Factors 44\u003c\/p\u003e \u003cp\u003e2.2.4 Medicinal Chemistry Can Modulate Immunostimulation 45\u003c\/p\u003e \u003cp\u003e2.2.5 Medicinal Chemistry Can Improve RNase H Cleavage Specificity 46\u003c\/p\u003e \u003cp\u003e2.2.6 Medicinal Chemistry Can Improve Cellular Uptake and Subcellular Trafficking 47\u003c\/p\u003e \u003cp\u003e2.3 Chemical Modifications of Current Importance by Structural Class 48\u003c\/p\u003e \u003cp\u003e2.3.1 Sugar Modifications 48\u003c\/p\u003e \u003cp\u003e2.3.1.1 2′‐Modified Ribose Sugars 48\u003c\/p\u003e \u003cp\u003e2.3.1.2 2′‐Modified Arabinose Sugars 50\u003c\/p\u003e \u003cp\u003e2.3.1.3 2′,4′‐Difluorinated Nucleosides 50\u003c\/p\u003e \u003cp\u003e2.3.1.4 Constrained Nucleotides 50\u003c\/p\u003e \u003cp\u003e2.3.1.5 Sugars with Expanded Ring Size 53\u003c\/p\u003e \u003cp\u003e2.3.2 Phosphate Modifications 54\u003c\/p\u003e \u003cp\u003e2.3.2.1 Phosphorothioate 54\u003c\/p\u003e \u003cp\u003e2.3.2.2 Other Charged Phosphate Analogues 58\u003c\/p\u003e \u003cp\u003e2.3.2.3 Neutral Mimics of the Phosphate Linkage 58\u003c\/p\u003e \u003cp\u003e2.3.2.4 Metabolically Stable 5′‐Phosphate Analogues 60\u003c\/p\u003e \u003cp\u003e2.3.3 Total Replacement of the Sugar‐Phosphate Backbone 61\u003c\/p\u003e \u003cp\u003e2.3.4 Nucleobase Modifications 62\u003c\/p\u003e \u003cp\u003e2.3.4.1 Sulfur‐Modified Nucleobases 63\u003c\/p\u003e \u003cp\u003e2.3.4.2 5‐Modified Pyrimidines 63\u003c\/p\u003e \u003cp\u003e2.3.4.3 Nucleobases with Expanded Hydrogen Bonding Networks 65\u003c\/p\u003e \u003cp\u003e2.3.5 Assembly of Oligonucleotides into Multimeric Structures 66\u003c\/p\u003e \u003cp\u003e2.4 Conclusion 67\u003c\/p\u003e \u003cp\u003eReferences 69\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Cellular Pharmacology of Antisense Oligonucleotides 91\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eXin Ming\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Introduction91\u003c\/p\u003e \u003cp\u003e3.2 Molecular Mechanisms of Antisense Oligonucleotides 92\u003c\/p\u003e \u003cp\u003e3.2.1 Classic Antisense Oligonucleotides 92\u003c\/p\u003e \u003cp\u003e3.2.2 siRNA 94\u003c\/p\u003e \u003cp\u003e3.2.3 Splice Switching Oligonucleotides 94\u003c\/p\u003e \u003cp\u003e3.2.4 microRNA Antagomirs 95\u003c\/p\u003e \u003cp\u003e3.2.5 lncRNAs Antagomirs 95\u003c\/p\u003e \u003cp\u003e3.3 Cellular Pharmacology of Antisense Oligonucleotides 96\u003c\/p\u003e \u003cp\u003e3.3.1 Endocytosis of Free Oligonucleotides 98\u003c\/p\u003e \u003cp\u003e3.3.2 Endocytosis of Oligonucleotide Conjugates 98\u003c\/p\u003e \u003cp\u003e3.3.3 Uptake and Trafficking of Oligonucleotides Incorporated into Nanocarriers 100\u003c\/p\u003e \u003cp\u003e3.4 Conclusion 101\u003c\/p\u003e \u003cp\u003eReferences 101\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides 107\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eHelen Lightfoot, Anneliese Schneider, and Jonathan Hall\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 107\u003c\/p\u003e \u003cp\u003e4.2 Pharmacokinetic Properties of Antisense Oligonucleotides 108\u003c\/p\u003e \u003cp\u003e4.2.1 Protein Binding 109\u003c\/p\u003e \u003cp\u003e4.2.2 Dose Dependency of ASO Pharmacokinetics 110\u003c\/p\u003e \u003cp\u003e4.2.3 Absorption 110\u003c\/p\u003e \u003cp\u003e4.2.4 Distribution 111\u003c\/p\u003e \u003cp\u003e4.2.5 Metabolism and Excretion 112\u003c\/p\u003e \u003cp\u003e4.3 Pharmacodynamic Properties of Antisense Oligonucleotides 113\u003c\/p\u003e \u003cp\u003e4.3.1 ASO Target Selection and Validation 114\u003c\/p\u003e \u003cp\u003e4.3.2 Mechanisms of Action 117\u003c\/p\u003e \u003cp\u003e4.3.3 Biomarkers and PD Endpoints 118\u003c\/p\u003e \u003cp\u003e4.4 PD and PK Results and Strategies of ASOs in Clinical Development 119\u003c\/p\u003e \u003cp\u003e4.4.1 Genetic Diseases 122\u003c\/p\u003e \u003cp\u003e4.4.1.1 Mipomersen, Apolipoprotein B‐100, and Hypercholesterolemia 122\u003c\/p\u003e \u003cp\u003e4.4.1.2 Drisapersen, Dystrophin, and Duchenne Muscular Dystrophy (DMD) 123\u003c\/p\u003e \u003cp\u003e4.4.2 Infectious Diseases 125\u003c\/p\u003e \u003cp\u003e4.4.2.1 Miravirsen, miR‐122, and Hepatitis C Virus (HCV) 125\u003c\/p\u003e \u003cp\u003e4.4.3 Cancer 126\u003c\/p\u003e \u003cp\u003e4.4.3.1 Custirsen, Clusterin, and Cancer 126\u003c\/p\u003e \u003cp\u003e4.4.3.2 LY2181308 (ISIS‐23722), Survivin, and Cancer 127\u003c\/p\u003e \u003cp\u003e4.5 Summary and Conclusions 128\u003c\/p\u003e \u003cp\u003eReferences 130\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Tissue Distribution, Metabolism, and Clearance 137\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eMehrdad Dirin and Johannes Winkler\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction137\u003c\/p\u003e \u003cp\u003e5.2 Tissue Distribution 138\u003c\/p\u003e \u003cp\u003e5.2.1 Dermal Delivery 138\u003c\/p\u003e \u003cp\u003e5.2.2 Ocular Delivery 139\u003c\/p\u003e \u003cp\u003e5.2.3 Oral Administration 139\u003c\/p\u003e \u003cp\u003e5.2.4 Intrathecal Delivery 141\u003c\/p\u003e \u003cp\u003e5.2.5 Intravesical Administration 142\u003c\/p\u003e \u003cp\u003e5.2.6 Pulmonary Administration 142\u003c\/p\u003e \u003cp\u003e5.2.7 Distribution to Muscular Tissue 143\u003c\/p\u003e \u003cp\u003e5.2.8 Intravenous Administration 144\u003c\/p\u003e \u003cp\u003e5.3 Cellular Uptake 146\u003c\/p\u003e \u003cp\u003e5.4 Metabolism and Clearance 148\u003c\/p\u003e \u003cp\u003e5.4.1 Phosphorothioates Including 2′‐Modifications 148\u003c\/p\u003e \u003cp\u003e5.4.2 Phosphorodiamidate Morpholino Oligonucleotides 149\u003c\/p\u003e \u003cp\u003e5.5 Conclusion 150\u003c\/p\u003e \u003cp\u003eReferences 151\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Hybridization‐Independent Effects: Principles and Specific Considerations for Oligonucleotide Drugs 161\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eNicolay Ferrari\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Background 161\u003c\/p\u003e \u003cp\u003e6.2 Mechanisms of Hybridization‐independent Toxicities 162\u003c\/p\u003e \u003cp\u003e6.2.1 Effects Related to Oligonucleotide Sequence 162\u003c\/p\u003e \u003cp\u003e6.2.1.1 Unmethylated CpG Motifs 162\u003c\/p\u003e \u003cp\u003e6.2.1.2 Poly‐G Sequences 163\u003c\/p\u003e \u003cp\u003e6.2.1.3 DNA Triplex‐forming Oligonucleotides 164\u003c\/p\u003e \u003cp\u003e6.2.1.4 Other Motifs 164\u003c\/p\u003e \u003cp\u003e6.2.2 Effects Related to Oligonucleotide Chemistry 164\u003c\/p\u003e \u003cp\u003e6.2.2.1 Phosphorothioate Oligonucleotides 165\u003c\/p\u003e \u003cp\u003e6.2.2.2 Effects of Other Chemical Modifications 171\u003c\/p\u003e \u003cp\u003e6.3 Hybridization‐independent Effects Following Local Delivery of Oligonucleotides 171\u003c\/p\u003e \u003cp\u003e6.3.1 Pulmonary Toxicity of Inhaled Oligonucleotides 171\u003c\/p\u003e \u003cp\u003e6.3.1.1 Specific Considerations for Inhaled Oligonucleotides 173\u003c\/p\u003e \u003cp\u003e6.3.2 Approaches to Reduce Hybridization‐independent Class Effects of Inhaled Oligonucleotides 175\u003c\/p\u003e \u003cp\u003e6.3.2.1 Mixed Phosphorothioate\/Phosphodiester Oligonucleotides 175\u003c\/p\u003e \u003cp\u003e6.4 Conclusion 180\u003c\/p\u003e \u003cp\u003eReferences 180\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Hybridization‐Dependent Effects: The Prediction, Evaluation,and Consequences of Unintended Target Hybridization 191\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eJeremy D. A. Kitson, Piotr J. Kamola, and Lauren Kane\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 191\u003c\/p\u003e \u003cp\u003e7.1.1 Scope of this Review: RNase H1‐dependent ASOs 192\u003c\/p\u003e \u003cp\u003e7.2 Specificity Studies with ASOs 192\u003c\/p\u003e \u003cp\u003e7.3 Implications of the Nuclear Site of Action of RNase H1 194\u003c\/p\u003e \u003cp\u003e7.3.1 Confirmation of Unintended Targets within Introns 195\u003c\/p\u003e \u003cp\u003e7.4 Mechanism of OTE 196\u003c\/p\u003e \u003cp\u003e7.5 Determining the Extent that Accessibility, Affinity and, Mismatch Tolerance Contribute to Off‐target Activity 198\u003c\/p\u003e \u003cp\u003e7.5.1 Accessibility 198\u003c\/p\u003e \u003cp\u003e7.5.2 Affinity 199\u003c\/p\u003e \u003cp\u003e7.5.3 The Interaction of RNase H1 with the RNA\/ASO Duplex 200\u003c\/p\u003e \u003cp\u003e7.5.4 Mismatch Tolerance 202\u003c\/p\u003e \u003cp\u003e7.6 Consequences of Unintended Transcript Knockdown: \u003ci\u003eIn Vivo\u003c\/i\u003e and \u003ci\u003eIn Vitro\u003c\/i\u003e Toxicity 203\u003c\/p\u003e \u003cp\u003e7.7 Identification and Evaluation of Putative OTEs 207\u003c\/p\u003e \u003cp\u003e7.7.1 Computational Prediction of Unintended Targeting 207\u003c\/p\u003e \u003cp\u003e7.7.1.1 Database Creation 209\u003c\/p\u003e \u003cp\u003e7.7.1.2 Sequence Alignments 209\u003c\/p\u003e \u003cp\u003e7.7.1.3 Cross‐species Off‐target Homology 210\u003c\/p\u003e \u003cp\u003e7.7.1.4 Results Filtering and Annotation 211\u003c\/p\u003e \u003cp\u003e7.7.1.5 RNA Structure and Target Accessibility 211\u003c\/p\u003e \u003cp\u003e7.7.1.6 ASO–Target Duplex Thermodynamics 213\u003c\/p\u003e \u003cp\u003e7.7.1.7 Computational Framework for OTEs 214\u003c\/p\u003e \u003cp\u003e7.7.1.8 \u003ci\u003eIn Vitro\u003c\/i\u003e Screening for OTEs 214\u003c\/p\u003e \u003cp\u003e7.7.1.9 Methods for Measuring Gene Expression 216\u003c\/p\u003e \u003cp\u003e7.8 Summary 216\u003c\/p\u003e \u003cp\u003eAcknowledgments 217\u003c\/p\u003e \u003cp\u003eReferences 218\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Class‐Related Proinflammatory Effects 227\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eRosanne Seguin\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 Introduction 227\u003c\/p\u003e \u003cp\u003e8.2 Proinflammatory Effects of ASO for Consideration in Drug Development 228\u003c\/p\u003e \u003cp\u003e8.2.1 Activation of the Complement Cascade in Monkeys 228\u003c\/p\u003e \u003cp\u003e8.2.2 Cytokine Release 229\u003c\/p\u003e \u003cp\u003e8.2.3 Mononuclear Cellular Infiltrate 232\u003c\/p\u003e \u003cp\u003e8.2.4 Hematological Changes 236\u003c\/p\u003e \u003cp\u003e8.2.5 Immunogenicity 237\u003c\/p\u003e \u003cp\u003e8.3 Conclusions 238\u003c\/p\u003e \u003cp\u003eReferences 239\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Exaggerated Pharmacology 243\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eAlain Guimond and Doug Kornbrust\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 243\u003c\/p\u003e \u003cp\u003e9.2 Regulatory Expectations 244\u003c\/p\u003e \u003cp\u003e9.3 Scope of EP Assessment 245\u003c\/p\u003e \u003cp\u003e9.3.1 Species Selection 245\u003c\/p\u003e \u003cp\u003e9.3.2 Determination of Pharmacologic Relevance 247\u003c\/p\u003e \u003cp\u003e9.4 EP Evaluation Strategies 248\u003c\/p\u003e \u003cp\u003e9.4.1 Concerns About the Use of Animal‐active Analogues 248\u003c\/p\u003e \u003cp\u003e9.4.2 Animal‐active Analogues in Reproductive and\/or Carcinogenicity Studies 250\u003c\/p\u003e \u003cp\u003e9.4.3 Other Considerations for Use of Animal Analogues 250\u003c\/p\u003e \u003cp\u003e9.4.4 The Use of Inactive Analogues as Control Articles 250\u003c\/p\u003e \u003cp\u003e9.4.5 The Role of Formulations 251\u003c\/p\u003e \u003cp\u003e9.4.6 Aptamer Oligonucleotides 251\u003c\/p\u003e \u003cp\u003e9.4.7 Immunostimulatory Oligonucleotides 252\u003c\/p\u003e \u003cp\u003e9.4.8 MicroRNA 253\u003c\/p\u003e \u003cp\u003e9.5 Conclusions 254\u003c\/p\u003e \u003cp\u003eReferences 255\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Genotoxicity Tests for Novel Oligonucleotide‐Based Therapeutics 257\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eCindy L. Berman, Scott A. Barros, Sheila M. Galloway, Peter Kasper, Frederick B. Oleson, Catherine C. Priestley, Kevin S. Sweder, Michael J. Schlosser, and Zhanna Sobol\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 257\u003c\/p\u003e \u003cp\u003e10.1.1 History of Regulatory Guidance on Genotoxicity Testing 259\u003c\/p\u003e \u003cp\u003e10.1.2 Relevance of the Standard Genotoxicity Test Battery to ONs 260\u003c\/p\u003e \u003cp\u003e10.2 Experience with ONs in the Standard Battery 262\u003c\/p\u003e \u003cp\u003e10.2.1 ON Chemical Classes Tested for Genotoxicity 264\u003c\/p\u003e \u003cp\u003e10.2.2 Conclusions Based on the Database 265\u003c\/p\u003e \u003cp\u003e10.3 OSWG Recommendation for Genotoxicity Testing of ONs 266\u003c\/p\u003e \u003cp\u003e10.3.1 Recommended Test Battery 266\u003c\/p\u003e \u003cp\u003e10.3.2 Requirement for Evidence for Uptake 270\u003c\/p\u003e \u003cp\u003e10.3.3 Need for Testing of ONs 271\u003c\/p\u003e \u003cp\u003e10.3.3.1 Nonconjugated ONs in Simple Aqueous Formulations 271\u003c\/p\u003e \u003cp\u003e10.3.3.2 ONs in Complex Formulations or Conjugates 272\u003c\/p\u003e \u003cp\u003e10.3.4 Recommended Test Conditions 273\u003c\/p\u003e \u003cp\u003e10.3.4.1 Top Concentration for \u003ci\u003eIn Vitro\u003c\/i\u003e Tests 273\u003c\/p\u003e \u003cp\u003e10.3.4.2 Use of S‐9 in \u003ci\u003eIn Vitro\u003c\/i\u003e Tests 273\u003c\/p\u003e \u003cp\u003e10.3.4.3 In Vivo Tests 274\u003c\/p\u003e \u003cp\u003e10.4 Triplex Formation 275\u003c\/p\u003e \u003cp\u003e10.4.1 Biochemical Requirements for Triplex Formation 275\u003c\/p\u003e \u003cp\u003e10.4.2 Assessment of New ONs for Triplex Formation 277\u003c\/p\u003e \u003cp\u003e10.5 Impurities 278\u003c\/p\u003e \u003cp\u003e10.5.1 ON‐Related Impurities 278\u003c\/p\u003e \u003cp\u003e10.5.2 Potentially Mutagenic Impurities 278\u003c\/p\u003e \u003cp\u003e10.6 Conclusions 279\u003c\/p\u003e \u003cp\u003eAcknowledgments 280\u003c\/p\u003e \u003cp\u003eReferences 280\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Reproductive and Developmental Toxicity Testing Strategies for Oligonucleotide‐Based Therapeutics 287\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eTacey E.K. White and Joy Cavagnaro\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Introduction 287\u003c\/p\u003e \u003cp\u003e11.2 General Design of Reproductive and Developmental Toxicity Studies 289\u003c\/p\u003e \u003cp\u003e11.3 Product Attributes of Oligonucleotide Drugs 291\u003c\/p\u003e \u003cp\u003e11.4 The Role of Intended Pharmacology in Reproductive and Developmental Effects 293\u003c\/p\u003e \u003cp\u003e11.5 Selection of Animal Species 294\u003c\/p\u003e \u003cp\u003e11.5.1 Design and Use of Animal‐active Analogues 294\u003c\/p\u003e \u003cp\u003e11.6 Justification of Dosing Regimen 296\u003c\/p\u003e \u003cp\u003e11.7 Exposure Assessment 297\u003c\/p\u003e \u003cp\u003e11.8 Subclass‐ specific Considerations 298\u003c\/p\u003e \u003cp\u003e11.8.1 Single‐stranded DNA Antisense Oligonucleotides 299\u003c\/p\u003e \u003cp\u003e11.8.2 CpG and Immunostimulatory (IS) Oligonucleotides 300\u003c\/p\u003e \u003cp\u003e11.8.3 microRNA Mimetics\/Antagonists and siRNAs 301\u003c\/p\u003e \u003cp\u003e11.8.4 Aptamer Oligonucleotides 303\u003c\/p\u003e \u003cp\u003e11.9 Conclusions 304\u003c\/p\u003e \u003cp\u003eAcknowledgments 305\u003c\/p\u003e \u003cp\u003eReferences 305\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Specific Considerations for Preclinical Development of Inhaled Oligonucleotides 311\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eNicolay Ferrar \u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Background 311\u003c\/p\u003e \u003cp\u003e12.2 Oligonucleotide Delivery Systems 312\u003c\/p\u003e \u003cp\u003e12.2.1 Inhalation Exposure Systems 312\u003c\/p\u003e \u003cp\u003e12.2.2 Intratracheal Aerosol Instillation 313\u003c\/p\u003e \u003cp\u003e12.3 Repeat‐dose Toxicity 314\u003c\/p\u003e \u003cp\u003e12.3.1 General Principles 314\u003c\/p\u003e \u003cp\u003e12.3.2 Recovery Phase 317\u003c\/p\u003e \u003cp\u003e12.4 Toxicokinetics 319\u003c\/p\u003e \u003cp\u003e12.5 Safety Pharmacology 322\u003c\/p\u003e \u003cp\u003e12.5.1 Respiratory System 323\u003c\/p\u003e \u003cp\u003e12.5.2 Cardiovascular and Central Nervous Systems 324\u003c\/p\u003e \u003cp\u003e12.6 Additional Testing 326\u003c\/p\u003e \u003cp\u003e12.6.1 Complement Activation 326\u003c\/p\u003e \u003cp\u003e12.6.2 Proinflammatory Effects 327\u003c\/p\u003e \u003cp\u003e12.7 Conclusion 328\u003c\/p\u003e \u003cp\u003eReferences 328\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Lessons Learned in Oncology Programs 331\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eCindy Jacobs, Monica Krieger, Patricia S. Stewart, Karen D. Wisont,and Scott Cormack\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 331\u003c\/p\u003e \u003cp\u003e13.2 Clinical Development of First‐generation ASOs 332\u003c\/p\u003e \u003cp\u003e13.2.1 Aprinocarsen 332\u003c\/p\u003e \u003cp\u003e13.2.2 Oblimersen 334\u003c\/p\u003e \u003cp\u003e13.2.3 Challenges Associated with First‐generation ASOs 335\u003c\/p\u003e \u003cp\u003e13.3 Clinical Development of Second‐generation ASOs 336\u003c\/p\u003e \u003cp\u003e13.3.1 Custirsen 337\u003c\/p\u003e \u003cp\u003e13.3.2 Lessons Learned from Custirsen Clinical Development 343\u003c\/p\u003e \u003cp\u003e13.3.3 Apatorsen 344\u003c\/p\u003e \u003cp\u003e13.3.4 Bladder Cancer 346\u003c\/p\u003e \u003cp\u003e13.3.5 Lung Cancer 346\u003c\/p\u003e \u003cp\u003e13.3.6 Pancreatic Cancer 347\u003c\/p\u003e \u003cp\u003e13.3.7 Prostate Cancer 347\u003c\/p\u003e \u003cp\u003e13.4 Regulatory Considerations 348\u003c\/p\u003e \u003cp\u003e13.5 Future Opportunities for ASOs as Therapeutic Agents for Cancer Treatment 349\u003c\/p\u003e \u003cp\u003eReferences 349\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Inhaled Antisense for Treatment of Respiratory Disease 355\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eGail M. Gauvreau, Beth E. Davis, and John Paul Oliveria\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 355\u003c\/p\u003e \u003cp\u003e14.2 Atopic Asthma 355\u003c\/p\u003e \u003cp\u003e14.2.1 Pharmacotherapy of Asthma 356\u003c\/p\u003e \u003cp\u003e14.2.2 Anti‐IL‐5 Monoclonal Antibodies 357\u003c\/p\u003e \u003cp\u003e14.2.3 Anti‐IL‐4\/13 Monoclonal Antibodies 359\u003c\/p\u003e \u003cp\u003e14.3 Antisense Oligonucleotides in Animal Models 361\u003c\/p\u003e \u003cp\u003e14.3.1 CpG Immunostimulatory Sequences 361\u003c\/p\u003e \u003cp\u003e14.3.2 Antisense to Receptors on Eosinophils 366\u003c\/p\u003e \u003cp\u003e14.3.3 Antisense to IL‐4 and IL‐13 Receptors 368\u003c\/p\u003e \u003cp\u003e14.3.4 Summary of Antisense Oligonucleotides in Animal Models 368\u003c\/p\u003e \u003cp\u003e14.4 Clinical Data 369\u003c\/p\u003e \u003cp\u003e14.4.1 Allergen Challenge: A Model of Asthma Exacerbation 369\u003c\/p\u003e \u003cp\u003e14.4.2 Allergen Challenge for Evaluation of Efficacy 369\u003c\/p\u003e \u003cp\u003e14.4.3 1018 Immunostimulatory Sequence 370\u003c\/p\u003e \u003cp\u003e14.4.3.1 Study Design for 1018 ISS 370\u003c\/p\u003e \u003cp\u003e14.4.3.2 Results for 1018 ISS 371\u003c\/p\u003e \u003cp\u003e14.4.4 AIR645 372\u003c\/p\u003e \u003cp\u003e14.4.4.1 Study Design for AIR645 373\u003c\/p\u003e \u003cp\u003e14.4.4.2 Results for AIR645 373\u003c\/p\u003e \u003cp\u003e14.4.5 TPI ASM8 374\u003c\/p\u003e \u003cp\u003e14.4.5.1 Mechanism of TPI ASM8 374\u003c\/p\u003e \u003cp\u003e14.4.5.2 Study #1 for TPI ASM8 375\u003c\/p\u003e \u003cp\u003e14.4.5.3 Study #2 for TPI ASM8 377\u003c\/p\u003e \u003cp\u003e14.5 General\u003c\/p\u003e \u003cp\u003eConclusion 378\u003c\/p\u003e \u003cp\u003eReferences 378\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 Antisense Oligonucleotides for Treatment of Neurological Diseases 389\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eRosanne Seguin\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction 389\u003c\/p\u003e \u003cp\u003e15.1.1 Delivery of ASO to Central Nervous System 389\u003c\/p\u003e \u003cp\u003e15.2 Potential ASO Therapies in Neurodegenerative Diseases 390\u003c\/p\u003e \u003cp\u003e15.2.1 Spinal Muscular Atrophy (SMA) 390\u003c\/p\u003e \u003cp\u003e15.2.2 Amyotrophic Lateral Sclerosis (ALS) 393\u003c\/p\u003e \u003cp\u003e15.2.3 Huntington’s Disease (HD) 396\u003c\/p\u003e \u003cp\u003e15.2.4 Muscular Sclerosis (MS) 399\u003c\/p\u003e \u003cp\u003e15.2.5 Alzheimer’s Disease (AD) 401\u003c\/p\u003e \u003cp\u003e15.3 Conclusion 403\u003c\/p\u003e \u003cp\u003eReferences 403\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Nucleic Acids as Adjuvants 411\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eKevin Brown, Montserrat Puig, Lydia Haile, Derek Ireland, John Martucci, and Daniela Verthelyi\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 411\u003c\/p\u003e \u003cp\u003e16.1.1 TLR as Nucleic Acid‐Sensing Pathogen Recognition Receptors (PRR) 412\u003c\/p\u003e \u003cp\u003e16.2 Categories of Nucleic Acid Adjuvants 413\u003c\/p\u003e \u003cp\u003e16.2.1 DNA‐Based Adjuvants and Vaccine Studies in Mice 417\u003c\/p\u003e \u003cp\u003e16.2.2 Classes of CpG ODN that Activate Human TLR9 421\u003c\/p\u003e \u003cp\u003e16.2.3 Preclinical Studies with Human CpG ODN 422\u003c\/p\u003e \u003cp\u003e16.2.4 Safety Issues Raised in Animal Models 424\u003c\/p\u003e \u003cp\u003e16.2.5 Clinical Trial Experience 425\u003c\/p\u003e \u003cp\u003e16.2.6 Safety Issues from Human Clinical Trials 427\u003c\/p\u003e \u003cp\u003e16.2.7 Novel Delivery Systems for CpG ODN as Adjuvants 427\u003c\/p\u003e \u003cp\u003e16.3 Conclusion 429\u003c\/p\u003e \u003cp\u003eAcknowledgments 429\u003c\/p\u003e \u003cp\u003eReferences 430\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Splice‐Switching Oligonucleotides 445\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eIsabella Gazzoli and Annemieke Aartsma‐Rus\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction of Splice Switching 445\u003c\/p\u003e \u003cp\u003e17.1.1 Correct Cryptic Splicing 446\u003c\/p\u003e \u003cp\u003e17.1.1.1 β‐Thalassemia 446\u003c\/p\u003e \u003cp\u003e17.1.1.2 Cystic Fibrosis 450\u003c\/p\u003e \u003cp\u003e17.1.2 Isoform Switching 451\u003c\/p\u003e \u003cp\u003e17.1.2.1 Anticancer 451\u003c\/p\u003e \u003cp\u003e17.1.2.2 Tauopathies 452\u003c\/p\u003e \u003cp\u003e17.1.3 Induce Exon Inclusion 452\u003c\/p\u003e \u003cp\u003e17.1.3.1 Tumorigenesis 452\u003c\/p\u003e \u003cp\u003e17.1.3.2 Spinal Muscular Atrophy (SMA) 453\u003c\/p\u003e \u003cp\u003e17.1.4 Reading Frame Correction 454\u003c\/p\u003e \u003cp\u003e17.1.4.1 Duchenne Muscular Dystrophy 454\u003c\/p\u003e \u003cp\u003e17.1.4.2 Dysferlinopathies 455\u003c\/p\u003e \u003cp\u003e17.1.5 Knockdown 456\u003c\/p\u003e \u003cp\u003e17.1.5.1 Atherosclerosis 456\u003c\/p\u003e \u003cp\u003e17.1.5.2 Myostatin‐Related Muscle Hypertrophy 457\u003c\/p\u003e \u003cp\u003e17.2 Preclinical and Clinical Development of Splice‐switching Oligos 457\u003c\/p\u003e \u003cp\u003e17.2.1 Introduction to Different Chemistries to be Used for Splice Switching 457\u003c\/p\u003e \u003cp\u003e17.2.2 AON Targets 459\u003c\/p\u003e \u003cp\u003e17.2.3 AON Development for DMD 460\u003c\/p\u003e \u003cp\u003e17.2.4 2′‐O‐Methyl Phosphorothioate AONs 461\u003c\/p\u003e \u003cp\u003e17.2.4.1 Animal Studies 461\u003c\/p\u003e \u003cp\u003e17.2.4.2 Human Studies 463\u003c\/p\u003e \u003cp\u003e17.2.5 Phosphorodiamidate Morpholino Oligos 466\u003c\/p\u003e \u003cp\u003e17.2.5.1 Animal Studies 466\u003c\/p\u003e \u003cp\u003e17.2.5.2 Human Studies 467\u003c\/p\u003e \u003cp\u003e17.2.6 Other Chemistries 468\u003c\/p\u003e \u003cp\u003e17.2.6.1 Peptide‐Conjugated PMOs 468\u003c\/p\u003e \u003cp\u003e17.2.7 Preclinical and Clinical Studies for Other Diseases 470\u003c\/p\u003e \u003cp\u003e17.2.7.1 Spinal Muscular Atrophy (SMA) 470\u003c\/p\u003e \u003cp\u003e17.2.8 Biomarkers 472\u003c\/p\u003e \u003cp\u003e17.3 Future Directions 474\u003c\/p\u003e \u003cp\u003eConflictof Interest 475\u003c\/p\u003e \u003cp\u003eAcknowledgments 475\u003c\/p\u003e \u003cp\u003eReferences 475\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 CMC Aspects for the Clinical Development of Spiegelmers 491\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003ci\u003eStefan Vonhoff\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction 491\u003c\/p\u003e \u003cp\u003e18.2 Technology (Mirror‐imaged SELEX Process) Selected Pharmaceutical Properties 492\u003c\/p\u003e \u003cp\u003e18.3 Preclinical Efficacy Data for Spiegelmers 494\u003c\/p\u003e \u003cp\u003e18.4 Clinical Development 504\u003c\/p\u003e \u003cp\u003e18.4.1 Emapticap Pegol: NOX‐E36 504\u003c\/p\u003e \u003cp\u003e18.4.2 Olaptesed Pegol: NOX‐A12 506\u003c\/p\u003e \u003cp\u003e18.4.3 Lexaptepid Pegol: NOX‐H94 507\u003c\/p\u003e \u003cp\u003e18.5 CMC Aspects for the Development of Spiegelmers 508\u003c\/p\u003e \u003cp\u003e18.5.1 Discovery and Early Preclinical Stage 508\u003c\/p\u003e \u003cp\u003e18.5.2 Generic Manufacturing Process 509\u003c\/p\u003e \u003cp\u003e18.5.2.1 Solid‐phase Synthesis 510\u003c\/p\u003e \u003cp\u003e18.5.2.2 Deprotection 510\u003c\/p\u003e \u003cp\u003e18.5.2.3 Purification of the Intermediate Spiegelmer Prior to Pegylation 510\u003c\/p\u003e \u003cp\u003e18.5.2.4 Pegylation 510\u003c\/p\u003e \u003cp\u003e18.5.2.5 Purification of the Pegylated Spiegelmer 510\u003c\/p\u003e \u003cp\u003e18.5.3 CMC Aspects for the Selection of Development Candidates 511\u003c\/p\u003e \u003cp\u003e18.5.4 GMP Production of Spiegelmers 514\u003c\/p\u003e \u003cp\u003e18.5.4.1 Starting Materials 514\u003c\/p\u003e \u003cp\u003e18.5.4.2 Drug Substance 516\u003c\/p\u003e \u003cp\u003e18.5.4.3 Drug Product 516\u003c\/p\u003e \u003cp\u003e18.5.5 Analytical Methods for the Quality Control of Spiegelmers 517\u003c\/p\u003e \u003cp\u003e18.6 Future Prospects for Spiegelmer Therapeutics 521\u003c\/p\u003e \u003cp\u003eReferences 521\u003c\/p\u003e \u003cp\u003eIndex 527\u003c\/p\u003e","brand":"John Wiley \u0026 Sons Inc","offers":[{"title":"Default Title","offer_id":49406886314327,"sku":"9781118537336","price":161.06,"currency_code":"GBP","in_stock":false}],"url":"https:\/\/bookcurl.com\/products\/oligonucleotidebased-drugs-and-therapeutics-preclinical-and-clinical-considerations-for-development-9781118537336","provider":"Book Curl","version":"1.0","type":"link"}