Oligonucleotide-Based Drugs and Therapeutics (eBook, PDF)

Preclinical and Clinical Considerations for Development
Redaktion: Ferrari, Nicolay; Seguin, Rosanne

• Format: PDF

Produktbeschreibung

A comprehensive review of contemporary antisense oligonucleotides drugs and therapeutic principles, methods, applications, and research Oligonucleotide-based drugs, in particular antisense oligonucleotides, are part of a growing number of pharmaceutical and biotech programs progressing to treat a wide range of indications including cancer, cardiovascular, neurodegenerative, neuromuscular, and respiratory diseases, as well as other severe and rare diseases. Reviewing fundamentals and offering guidelines for drug discovery and development, this book is a practical guide covering all key aspects of this increasingly popular area of pharmacology and biotech and pharma research, from the basic science behind antisense oligonucleotides chemistry, toxicology, manufacturing, to safety assessments, the design of therapeutic protocols, to clinical experience. Antisense oligonucleotides are single strands of DNA or RNA that are complementary to a chosen sequence. While the idea of antisense oligonucleotides to target single genes dates back to the 1970's, most advances have taken place in recent years. The increasing number of antisense oligonucleotide programs in clinical development is a testament to the progress and understanding of pharmacologic, pharmacokinetic, and toxicologic properties as well as improvement in the delivery of oligonucleotides. This valuable book reviews the fundamentals of oligonucleotides, with a focus on antisense oligonucleotide drugs, and reports on the latest research underway worldwide. * Helps readers understand antisense molecules and their targets, biochemistry, and toxicity mechanisms, roles in disease, and applications for safety and therapeutics * Examines the principles, practices, and tools for scientists in both pre-clinical and clinical settings and how to apply them to antisense oligonucleotides * Provides guidelines for scientists in drug design and discovery to help improve efficiency, assessment, and the success of drug candidates * Includes interdisciplinary perspectives, from academia, industry, regulatory and from the fields of pharmacology, toxicology, biology, and medicinal chemistry Oligonucleotide-Based Drugs and Therapeutics belongs on the reference shelves of chemists, pharmaceutical scientists, chemical biologists, toxicologists and other scientists working in the pharmaceutical and biotechnology industries. It will also be a valuable resource for regulatory specialists and safety assessment professionals and an important reference for academic researchers and post-graduates interested in therapeutics, antisense therapy, and oligonucleotides.

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Produktdetails

• Verlag: John Wiley & Sons
• Seitenzahl: 576
• Erscheinungstermin: 6. Juni 2018
• Englisch
• ISBN-13: 9781119070290
• Artikelnr.: 53058833

Autorenporträt

Nicolay Ferrari, PhD, is the Executive Director of the Canadian Critical Care Trials Group, a Canadian investigator-lead research network, Quebec, Canada. A former Director of Research in Pharmacology at Topigen Pharmaceuticals, Inc, over twenty years of research experience, Dr. Ferrari is the co-inventor of six patents. Rosanne Seguin, PhD, is an Academic Associate at the Montreal Neurological Institute of McGill University, Montreal, Quebec, Canada. A former Director of Immunology and Development Support at Topigen Pharmaceuticals, Inc. Dr. Seguin has 20 years of research experience.

Inhaltsangabe

List of Contributors xvii Preface xxi Acknowledgments xxii 1 Mechanisms of
Oligonucleotide Actions 1 Annemieke Aartsma-Rus, Aimee L. Jackson, and
Arthur A. Levin 1.1 Introduction 1.2 Antisense Oligonucleotide Therapeutics
2 1.2.1 Antisense Activity Mediated by RNase H 2 1.2.2 The RNase H
Mechanism 2 1.2.3 Chemical Modifications to Enhance RNase H-mediated
Antisense Activity 3 1.3 Oligonucleotides that Sterically Block Translation
5 1.4 Oligonucleotides that Act Through the RNAi Pathway 5 1.4.1 The RISC
Pathway 5 1.4.2 Mechanisms of RISC-mediated Gene Silencing 8 1.5 Chemical
Modification of siRNAs and miRNAs 10 1.5.1 Delivery of Therapeutic siRNAs
or miRNAs 12 1.6 Clinical Use of Oligonucleotides that Act through the RNAi
Pathway 14 1.7 Oligonucleotides that Modulate Splicing 17 1.7.1 Pre-mRNA
Splicing and Disease 17 1.7.2 Mechanisms of Oligonucleotide-mediated
Splicing Modulation 17 1.7.3 Chemical Modifications that Enhance Activity
of Oligonucleotidebased Splicing Modulators 21 1.7.4 Clinical Applications
of Splicing Modulators 22 1.8 Conclusions 22 References 22 2 The Medicinal
Chemistry of Antisense Oligonucleotides 39 Jonathan K. Watts 2.1
Introduction:The Antisense Approach and the Need for Chemical Modification
39 2.1.1 How Does Medicinal Chemistry Apply to Oligonucleotides? 40 2.1.2
Chemistry and Toxicity 41 2.2 Why Chemically Modify an Oligonucleotide? 42
2.2.1 Medicinal Chemistry Can Increase Nuclease Stability 42 2.2.2
Medicinal Chemistry Can Tune Binding Affinity and Specificity 43 2.2.3
Medicinal Chemistry Can Change Interactions with Cellular Factors 44 2.2.4
Medicinal Chemistry Can Modulate Immunostimulation 45 2.2.5 Medicinal
Chemistry Can Improve RNase H Cleavage Specificity 46 2.2.6 Medicinal
Chemistry Can Improve Cellular Uptake and Subcellular Trafficking 47 2.3
Chemical Modifications of Current Importance by Structural Class 48 2.3.1
Sugar Modifications 48 2.3.1.1 2'-Modified Ribose Sugars 48 2.3.1.2
2'-Modified Arabinose Sugars 50 2.3.1.3 2',4'-Difluorinated Nucleosides 50
2.3.1.4 Constrained Nucleotides 50 2.3.1.5 Sugars with Expanded Ring Size
53 2.3.2 Phosphate Modifications 54 2.3.2.1 Phosphorothioate 54 2.3.2.2
Other Charged Phosphate Analogues 58 2.3.2.3 Neutral Mimics of the
Phosphate Linkage 58 2.3.2.4 Metabolically Stable 5'-Phosphate Analogues 60
2.3.3 Total Replacement of the Sugar-Phosphate Backbone 61 2.3.4 Nucleobase
Modifications 62 2.3.4.1 Sulfur-Modified Nucleobases 63 2.3.4.2 5-Modified
Pyrimidines 63 2.3.4.3 Nucleobases with Expanded Hydrogen Bonding Networks
65 2.3.5 Assembly of Oligonucleotides into Multimeric Structures 66 2.4
Conclusion 67 References 69 3 Cellular Pharmacology of Antisense
Oligonucleotides 91 Xin Ming 3.1 Introduction91 3.2 Molecular Mechanisms of
Antisense Oligonucleotides 92 3.2.1 Classic Antisense Oligonucleotides 92
3.2.2 siRNA 94 3.2.3 Splice Switching Oligonucleotides 94 3.2.4 microRNA
Antagomirs 95 3.2.5 lncRNAs Antagomirs 95 3.3 Cellular Pharmacology of
Antisense Oligonucleotides 96 3.3.1 Endocytosis of Free Oligonucleotides 98
3.3.2 Endocytosis of Oligonucleotide Conjugates 98 3.3.3 Uptake and
Trafficking of Oligonucleotides Incorporated into Nanocarriers 100 3.4
Conclusion 101 References 101 4 Pharmacokinetics and Pharmacodynamics of
Antisense Oligonucleotides 107 Helen Lightfoot, Anneliese Schneider, and
Jonathan Hall 4.1 Introduction 107 4.2 Pharmacokinetic Properties of
Antisense Oligonucleotides 108 4.2.1 Protein Binding 109 4.2.2 Dose
Dependency of ASO Pharmacokinetics 110 4.2.3 Absorption 110 4.2.4
Distribution 111 4.2.5 Metabolism and Excretion 112 4.3 Pharmacodynamic
Properties of Antisense Oligonucleotides 113 4.3.1 ASO Target Selection and
Validation 114 4.3.2 Mechanisms of Action 117 4.3.3 Biomarkers and PD
Endpoints 118 4.4 PD and PK Results and Strategies of ASOs in Clinical
Development 119 4.4.1 Genetic Diseases 122 4.4.1.1 Mipomersen,
Apolipoprotein B-100, and Hypercholesterolemia 122 4.4.1.2 Drisapersen,
Dystrophin, and Duchenne Muscular Dystrophy (DMD) 123 4.4.2 Infectious
Diseases 125 4.4.2.1 Miravirsen, miR-122, and Hepatitis C Virus (HCV) 125
4.4.3 Cancer 126 4.4.3.1 Custirsen, Clusterin, and Cancer 126 4.4.3.2
LY2181308 (ISIS-23722), Survivin, and Cancer 127 4.5 Summary and
Conclusions 128 References 130 5 Tissue Distribution, Metabolism, and
Clearance 137 Mehrdad Dirin and Johannes Winkler 5.1 Introduction137 5.2
Tissue Distribution 138 5.2.1 Dermal Delivery 138 5.2.2 Ocular Delivery 139
5.2.3 Oral Administration 139 5.2.4 Intrathecal Delivery 141 5.2.5
Intravesical Administration 142 5.2.6 Pulmonary Administration 142 5.2.7
Distribution to Muscular Tissue 143 5.2.8 Intravenous Administration 144
5.3 Cellular Uptake 146 5.4 Metabolism and Clearance 148 5.4.1
Phosphorothioates Including 2'-Modifications 148 5.4.2 Phosphorodiamidate
Morpholino Oligonucleotides 149 5.5 Conclusion 150 References 151 6
Hybridization-Independent Effects: Principles and Specific Considerations
for Oligonucleotide Drugs 161 Nicolay Ferrari 6.1 Background 161 6.2
Mechanisms of Hybridization-independent Toxicities 162 6.2.1 Effects
Related to Oligonucleotide Sequence 162 6.2.1.1 Unmethylated CpG Motifs 162
6.2.1.2 Poly-G Sequences 163 6.2.1.3 DNA Triplex-forming Oligonucleotides
164 6.2.1.4 Other Motifs 164 6.2.2 Effects Related to Oligonucleotide
Chemistry 164 6.2.2.1 Phosphorothioate Oligonucleotides 165 6.2.2.2 Effects
of Other Chemical Modifications 171 6.3 Hybridization-independent Effects
Following Local Delivery of Oligonucleotides 171 6.3.1 Pulmonary Toxicity
of Inhaled Oligonucleotides 171 6.3.1.1 Specific Considerations for Inhaled
Oligonucleotides 173 6.3.2 Approaches to Reduce Hybridization-independent
Class Effects of Inhaled Oligonucleotides 175 6.3.2.1 Mixed
Phosphorothioate/Phosphodiester Oligonucleotides 175 6.4 Conclusion 180
References 180 7 Hybridization-Dependent Effects: The Prediction,
Evaluation,and Consequences of Unintended Target Hybridization 191 Jeremy
D. A. Kitson, Piotr J. Kamola, and Lauren Kane 7.1 Introduction 191 7.1.1
Scope of this Review: RNase H1-dependent ASOs 192 7.2 Specificity Studies
with ASOs 192 7.3 Implications of the Nuclear Site of Action of RNase H1
194 7.3.1 Confirmation of Unintended Targets within Introns 195 7.4
Mechanism of OTE 196 7.5 Determining the Extent that Accessibility,
Affinity and, Mismatch Tolerance Contribute to Off-target Activity 198
7.5.1 Accessibility 198 7.5.2 Affinity 199 7.5.3 The Interaction of RNase
H1 with the RNA/ASO Duplex 200 7.5.4 Mismatch Tolerance 202 7.6
Consequences of Unintended Transcript Knockdown: In Vivo and In Vitro
Toxicity 203 7.7 Identification and Evaluation of Putative OTEs 207 7.7.1
Computational Prediction of Unintended Targeting 207 7.7.1.1 Database
Creation 209 7.7.1.2 Sequence Alignments 209 7.7.1.3 Cross-species
Off-target Homology 210 7.7.1.4 Results Filtering and Annotation 211
7.7.1.5 RNA Structure and Target Accessibility 211 7.7.1.6 ASO-Target
Duplex Thermodynamics 213 7.7.1.7 Computational Framework for OTEs 214
7.7.1.8 In Vitro Screening for OTEs 214 7.7.1.9 Methods for Measuring Gene
Expression 216 7.8 Summary 216 Acknowledgments 217 References 218 8
Class-Related Proinflammatory Effects 227 Rosanne Seguin 8.1 Introduction
227 8.2 Proinflammatory Effects of ASO for Consideration in Drug
Development 228 8.2.1 Activation of the Complement Cascade in Monkeys 228
8.2.2 Cytokine Release 229 8.2.3 Mononuclear Cellular Infiltrate 232 8.2.4
Hematological Changes 236 8.2.5 Immunogenicity 237 8.3 Conclusions 238
References 239 9 Exaggerated Pharmacology 243 Alain Guimond and Doug
Kornbrust 9.1 Introduction 243 9.2 Regulatory Expectations 244 9.3 Scope of
EP Assessment 245 9.3.1 Species Selection 245 9.3.2 Determination of
Pharmacologic Relevance 247 9.4 EP Evaluation Strategies 248 9.4.1 Concerns
About the Use of Animal-active Analogues 248 9.4.2 Animal-active Analogues
in Reproductive and/or Carcinogenicity Studies 250 9.4.3 Other
Considerations for Use of Animal Analogues 250 9.4.4 The Use of Inactive
Analogues as Control Articles 250 9.4.5 The Role of Formulations 251 9.4.6
Aptamer Oligonucleotides 251 9.4.7 Immunostimulatory Oligonucleotides 252
9.4.8 MicroRNA 253 9.5 Conclusions 254 References 255 10 Genotoxicity Tests
for Novel Oligonucleotide-Based Therapeutics 257 Cindy 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 10.1
Introduction 257 10.1.1 History of Regulatory Guidance on Genotoxicity
Testing 259 10.1.2 Relevance of the Standard Genotoxicity Test Battery to
ONs 260 10.2 Experience with ONs in the Standard Battery 262 10.2.1 ON
Chemical Classes Tested for Genotoxicity 264 10.2.2 Conclusions Based on
the Database 265 10.3 OSWG Recommendation for Genotoxicity Testing of ONs
266 10.3.1 Recommended Test Battery 266 10.3.2 Requirement for Evidence for
Uptake 270 10.3.3 Need for Testing of ONs 271 10.3.3.1 Nonconjugated ONs in
Simple Aqueous Formulations 271 10.3.3.2 ONs in Complex Formulations or
Conjugates 272 10.3.4 Recommended Test Conditions 273 10.3.4.1 Top
Concentration for In Vitro Tests 273 10.3.4.2 Use of S-9 in In Vitro Tests
273 10.3.4.3 In Vivo Tests 274 10.4 Triplex Formation 275 10.4.1
Biochemical Requirements for Triplex Formation 275 10.4.2 Assessment of New
ONs for Triplex Formation 277 10.5 Impurities 278 10.5.1 ON-Related
Impurities 278 10.5.2 Potentially Mutagenic Impurities 278 10.6 Conclusions
279 Acknowledgments 280 References 280 11 Reproductive and Developmental
Toxicity Testing Strategies for Oligonucleotide-Based Therapeutics 287
Tacey E.K. White and Joy Cavagnaro 11.1 Introduction 287 11.2 General
Design of Reproductive and Developmental Toxicity Studies 289 11.3 Product
Attributes of Oligonucleotide Drugs 291 11.4 The Role of Intended
Pharmacology in Reproductive and Developmental Effects 293 11.5 Selection
of Animal Species 294 11.5.1 Design and Use of Animal-active Analogues 294
11.6 Justification of Dosing Regimen 296 11.7 Exposure Assessment 297 11.8
Subclass- specific Considerations 298 11.8.1 Single-stranded DNA Antisense
Oligonucleotides 299 11.8.2 CpG and Immunostimulatory (IS) Oligonucleotides
300 11.8.3 microRNA Mimetics/Antagonists and siRNAs 301 11.8.4 Aptamer
Oligonucleotides 303 11.9 Conclusions 304 Acknowledgments 305 References
305 12 Specific Considerations for Preclinical Development of Inhaled
Oligonucleotides 311 Nicolay Ferrar 12.1 Background 311 12.2
Oligonucleotide Delivery Systems 312 12.2.1 Inhalation Exposure Systems 312
12.2.2 Intratracheal Aerosol Instillation 313 12.3 Repeat-dose Toxicity 314
12.3.1 General Principles 314 12.3.2 Recovery Phase 317 12.4 Toxicokinetics
319 12.5 Safety Pharmacology 322 12.5.1 Respiratory System 323 12.5.2
Cardiovascular and Central Nervous Systems 324 12.6 Additional Testing 326
12.6.1 Complement Activation 326 12.6.2 Proinflammatory Effects 327 12.7
Conclusion 328 References 328 13 Lessons Learned in Oncology Programs 331
Cindy Jacobs, Monica Krieger, Patricia S. Stewart, Karen D. Wisont,and
Scott Cormack 13.1 Introduction 331 13.2 Clinical Development of
First-generation ASOs 332 13.2.1 Aprinocarsen 332 13.2.2 Oblimersen 334
13.2.3 Challenges Associated with First-generation ASOs 335 13.3 Clinical
Development of Second-generation ASOs 336 13.3.1 Custirsen 337 13.3.2
Lessons Learned from Custirsen Clinical Development 343 13.3.3 Apatorsen
344 13.3.4 Bladder Cancer 346 13.3.5 Lung Cancer 346 13.3.6 Pancreatic
Cancer 347 13.3.7 Prostate Cancer 347 13.4 Regulatory Considerations 348
13.5 Future Opportunities for ASOs as Therapeutic Agents for Cancer
Treatment 349 References 349 14 Inhaled Antisense for Treatment of
Respiratory Disease 355 Gail M. Gauvreau, Beth E. Davis, and John Paul
Oliveria 14.1 Introduction 355 14.2 Atopic Asthma 355 14.2.1
Pharmacotherapy of Asthma 356 14.2.2 Anti-IL-5 Monoclonal Antibodies 357
14.2.3 Anti-IL-4/13 Monoclonal Antibodies 359 14.3 Antisense
Oligonucleotides in Animal Models 361 14.3.1 CpG Immunostimulatory
Sequences 361 14.3.2 Antisense to Receptors on Eosinophils 366 14.3.3
Antisense to IL-4 and IL-13 Receptors 368 14.3.4 Summary of Antisense
Oligonucleotides in Animal Models 368 14.4 Clinical Data 369 14.4.1
Allergen Challenge: A Model of Asthma Exacerbation 369 14.4.2 Allergen
Challenge for Evaluation of Efficacy 369 14.4.3 1018 Immunostimulatory
Sequence 370 14.4.3.1 Study Design for 1018 ISS 370 14.4.3.2 Results for
1018 ISS 371 14.4.4 AIR645 372 14.4.4.1 Study Design for AIR645 373
14.4.4.2 Results for AIR645 373 14.4.5 TPI ASM8 374 14.4.5.1 Mechanism of
TPI ASM8 374 14.4.5.2 Study #1 for TPI ASM8 375 14.4.5.3 Study #2 for TPI
ASM8 377 14.5 General Conclusion 378 References 378 15 Antisense
Oligonucleotides for Treatment of Neurological Diseases 389 Rosanne Seguin
15.1 Introduction 389 15.1.1 Delivery of ASO to Central Nervous System 389
15.2 Potential ASO Therapies in Neurodegenerative Diseases 390 15.2.1
Spinal Muscular Atrophy (SMA) 390 15.2.2 Amyotrophic Lateral Sclerosis
(ALS) 393 15.2.3 Huntington's Disease (HD) 396 15.2.4 Muscular Sclerosis
(MS) 399 15.2.5 Alzheimer's Disease (AD) 401 15.3 Conclusion 403 References
403 16 Nucleic Acids as Adjuvants 411 Kevin Brown, Montserrat Puig, Lydia
Haile, Derek Ireland, John Martucci, and Daniela Verthelyi 16.1
Introduction 411 16.1.1 TLR as Nucleic Acid-Sensing Pathogen Recognition
Receptors (PRR) 412 16.2 Categories of Nucleic Acid Adjuvants 413 16.2.1
DNA-Based Adjuvants and Vaccine Studies in Mice 417 16.2.2 Classes of CpG
ODN that Activate Human TLR9 421 16.2.3 Preclinical Studies with Human CpG
ODN 422 16.2.4 Safety Issues Raised in Animal Models 424 16.2.5 Clinical
Trial Experience 425 16.2.6 Safety Issues from Human Clinical Trials 427
16.2.7 Novel Delivery Systems for CpG ODN as Adjuvants 427 16.3 Conclusion
429 Acknowledgments 429 References 430 17 Splice-Switching Oligonucleotides
445 Isabella Gazzoli and Annemieke Aartsma-Rus 17.1 Introduction of Splice
Switching 445 17.1.1 Correct Cryptic Splicing 446 17.1.1.1 ß-Thalassemia
446 17.1.1.2 Cystic Fibrosis 450 17.1.2 Isoform Switching 451 17.1.2.1
Anticancer 451 17.1.2.2 Tauopathies 452 17.1.3 Induce Exon Inclusion 452
17.1.3.1 Tumorigenesis 452 17.1.3.2 Spinal Muscular Atrophy (SMA) 453
17.1.4 Reading Frame Correction 454 17.1.4.1 Duchenne Muscular Dystrophy
454 17.1.4.2 Dysferlinopathies 455 17.1.5 Knockdown 456 17.1.5.1
Atherosclerosis 456 17.1.5.2 Myostatin-Related Muscle Hypertrophy 457 17.2
Preclinical and Clinical Development of Splice-switching Oligos 457 17.2.1
Introduction to Different Chemistries to be Used for Splice Switching 457
17.2.2 AON Targets 459 17.2.3 AON Development for DMD 460 17.2.4
2'-O-Methyl Phosphorothioate AONs 461 17.2.4.1 Animal Studies 461 17.2.4.2
Human Studies 463 17.2.5 Phosphorodiamidate Morpholino Oligos 466 17.2.5.1
Animal Studies 466 17.2.5.2 Human Studies 467 17.2.6 Other Chemistries 468
17.2.6.1 Peptide-Conjugated PMOs 468 17.2.7 Preclinical and Clinical
Studies for Other Diseases 470 17.2.7.1 Spinal Muscular Atrophy (SMA) 470
17.2.8 Biomarkers 472 17.3 Future Directions 474 Conflictof Interest 475
Acknowledgments 475 References 475 18 CMC Aspects for the Clinical
Development of Spiegelmers 491 Stefan Vonhoff 18.1 Introduction 491 18.2
Technology (Mirror-imaged SELEX Process) Selected Pharmaceutical Properties
492 18.3 Preclinical Efficacy Data for Spiegelmers 494 18.4 Clinical
Development 504 18.4.1 Emapticap Pegol: NOX-E36 504 18.4.2 Olaptesed Pegol:
NOX-A12 506 18.4.3 Lexaptepid Pegol: NOX-H94 507 18.5 CMC Aspects for the
Development of Spiegelmers 508 18.5.1 Discovery and Early Preclinical Stage
508 18.5.2 Generic Manufacturing Process 509 18.5.2.1 Solid-phase Synthesis
510 18.5.2.2 Deprotection 510 18.5.2.3 Purification of the Intermediate
Spiegelmer Prior to Pegylation 510 18.5.2.4 Pegylation 510 18.5.2.5
Purification of the Pegylated Spiegelmer 510 18.5.3 CMC Aspects for the
Selection of Development Candidates 511 18.5.4 GMP Production of
Spiegelmers 514 18.5.4.1 Starting Materials 514 18.5.4.2 Drug Substance 516
18.5.4.3 Drug Product 516 18.5.5 Analytical Methods for the Quality Control
of Spiegelmers 517 18.6 Future Prospects for Spiegelmer Therapeutics 521
References 521 Index 527