Oligonucleotide based drugs and therapeutics preclinical and clinical considerations for development 1st Edition by Nicolay Ferrari, Rosanne Seguin ISBN 9781119070306 1119070309

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ISBN 10: 1119070309
ISBN 13: 9781119070306
Author: Nicolay Ferrari, Rosanne Seguin

Oligonucleotide based drugs and therapeutics preclinical and clinical considerations for development 1st Edition Table of contents:

1 Mechanisms of Oligonucleotide Actions

1.1 Introduction

1.2 Antisense Oligonucleotide Therapeutics

1.3 Oligonucleotides that Sterically Block Translation

1.4 Oligonucleotides that Act Through the RNAi Pathway

1.5 Chemical Modification of siRNAs and miRNAs

1.6 Clinical Use of Oligonucleotides that Act through the RNAi Pathway

1.7 Oligonucleotides that Modulate Splicing

1.8 Conclusions

References

2 The Medicinal Chemistry of Antisense Oligonucleotides

2.1 Introduction: The Antisense Approach and the Need for Chemical Modification

2.2 Why Chemically Modify an Oligonucleotide?

2.3 Chemical Modifications of Current Importance by Structural Class

2.4 Conclusion

References

3 Cellular Pharmacology of Antisense Oligonucleotides

3.1 Introduction

3.2 Molecular Mechanisms of Antisense Oligonucleotides

3.3 Cellular Pharmacology of Antisense Oligonucleotides

3.4 Conclusion

References

4 Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides

4.1 Introduction

4.2 Pharmacokinetic Properties of Antisense Oligonucleotides

4.3 Pharmacodynamic Properties of Antisense Oligonucleotides

4.4 PD and PK Results and Strategies of ASOs in Clinical Development

4.5 Summary and Conclusions

References

5 Tissue Distribution, Metabolism, and Clearance

5.1 Introduction

5.2 Tissue Distribution

5.3 Cellular Uptake

5.4 Metabolism and Clearance

5.5 Conclusion

References

6 Hybridization‐Independent Effects

6.1 Background

6.2 Mechanisms of Hybridization‐independent Toxicities

6.3 Hybridization‐independent Effects Following Local Delivery of Oligonucleotides

6.4 Conclusion

References

7 Hybridization‐Dependent Effects

7.1 Introduction

7.2 Specificity Studies with ASOs

7.3 Implications of the Nuclear Site of Action of RNase H1

7.4 Mechanism of OTE

7.5 Determining the Extent that Accessibility, Affinity and, Mismatch Tolerance Contribute to Off‐target Activity

7.6 Consequences of Unintended Transcript Knockdown: In Vivo and In Vitro Toxicity

7.7 Identification and Evaluation of Putative OTEs

7.8 Summary

Acknowledgments

References

8 Class‐Related Proinflammatory Effects

8.1 Introduction

8.2 Proinflammatory Effects of ASO for Consideration in Drug Development

8.3 Conclusions

References

9 Exaggerated Pharmacology

9.1 Introduction

9.2 Regulatory Expectations

9.3 Scope of EP Assessment

9.4 EP Evaluation Strategies

9.5 Conclusions

References

10 Genotoxicity Tests for Novel Oligonucleotide‐Based Therapeutics

10.1 Introduction

10.2 Experience with ONs in the Standard Battery

10.3 OSWG Recommendation for Genotoxicity Testing of ONs

10.4 Triplex Formation

10.5 Impurities

10.6 Conclusions

Acknowledgments

References

11 Reproductive and Developmental Toxicity Testing Strategies for Oligonucleotide‐Based Therapeutics

11.1 Introduction

11.2 General Design of Reproductive and Developmental Toxicity Studies

11.3 Product Attributes of Oligonucleotide Drugs

11.4 The Role of Intended Pharmacology in Reproductive and Developmental Effects

11.5 Selection of Animal Species

11.6 Justification of Dosing Regimen

11.7 Exposure Assessment

11.8 Subclass‐specific Considerations

11.9 Conclusions

Acknowledgments

References

12 Specific Considerations for Preclinical Development of Inhaled Oligonucleotides

12.1 Background

12.2 Oligonucleotide Delivery Systems

12.3 Repeat‐dose Toxicity

12.4 Toxicokinetics

12.5 Safety Pharmacology

12.6 Additional Testing

12.7 Conclusion

References

13 Lessons Learned in Oncology Programs

13.1 Introduction

13.2 Clinical Development of First‐generation ASOs

13.3 Clinical Development of Second‐generation ASOs

13.4 Regulatory Considerations

13.5 Future Opportunities for ASOs as Therapeutic Agents for Cancer Treatment

References

14 Inhaled Antisense for Treatment of Respiratory Disease

14.1 Introduction

14.2 Atopic Asthma

14.3 Antisense Oligonucleotides in Animal Models

14.4 Clinical Data

14.5 General Conclusion

References

15 Antisense Oligonucleotides for Treatment of Neurological Diseases

15.1 Introduction

15.2 Potential ASO Therapies in Neurodegenerative Diseases

15.3 Conclusion

References

16 Nucleic Acids as Adjuvants

16.1 Introduction

16.2 Categories of Nucleic Acid Adjuvants

16.3 Conclusion

Acknowledgments

References

17 Splice‐Switching Oligonucleotides

17.1 Introduction of Splice Switching

17.2 Preclinical and Clinical Development of Splice‐switching Oligos

17.3 Future Directions

Conflict of Interest

Acknowledgments

References

18 CMC Aspects for the Clinical Development of Spiegelmers

18.1 Introduction

18.2 Technology (Mirror‐imaged SELEX Process) Selected Pharmaceutical Properties

18.3 Preclinical Efficacy Data for Spiegelmers

18.4 Clinical Development

18.5 CMC Aspects for the Development of Spiegelmers

18.6 Future Prospects for Spiegelmer Therapeutics

References

Index

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