Preface ........................................................ ix
Acknowledgments ................................................ xi
The Editor ................................................... xiii
Contributors ................................................... xv
Part I Introduction ............................................. 1
Chapter 1. Mechanisms of Antisense Drug Action, an
Introduction ......................................... 3
Stanley T. Crooke, Timothy Vickers, Walt Lima,
and Hongjiang Wu
Chapter 2. The RNase H Mechanism ............................... 47
Walt Lima, Hongjiang Wu, and Stanley T. Crooke
Chapter 3. Small RNA Silencing Pathways ........................ 75
Alia Sigova and Phillip D. Zamore
Chapter 4. Splice Switching Oligonucleotides as
Potential Therapeutics .............................. 89
Peter Sazani, Maria A. Graziewicz, and Ryszard
Kole
Part II The Basics of Oligonucleotide-Based Therapeutics ...... 115
Chapter 5. Basic Principles of Antisense Drug Discovery ....... 117
Susan M. Freier and Andrew T. Watt
Chapter 6. The Medicinal Chemistry of Oligonucleotides ........ 143
Eric E. Swayze and Balkrishen Bhat
Chapter 7. Basic Principles of the Pharmacokinetics
of Antisense Oligonucleotide Drugs ................. 183
Arthur A. Levin, Rosie Z. Yu, and Richard
S. Geary
Chapter 8. Routes and Formulations for Delivery of
Antisense Oligonucleotides ......................... 217
Gregory E. Hardee, Lloyd G. Tillman, and
Richard S. Geary
Chapter 9. Liposomal Formulations for Nucleic Acid
Delivery ........................................... 237
Ian MacLachlan
Part III A. Hybridization-Based Drugs: Basic Properties
2'-0-Methoxyethyl Oligonucleotides ................ 271
Chapter 10.Pharmacological Properties of 2'-0-
Methoxyethyl-Modified Oligonucleotides ............. 273
C. Frank Bennett
Chapter 11.Pharmacokinetic/Pharmacodynamic Properties
of Phosphorothioate 2'-0-(2-Methoxyethyl)-
Modified Antisense Oligonucleotides in Animals
and Man ............................................ 305
Richard S. Geary, Rosie Z. Yu, Andrew
Siwkowski, and Arthur A. Levin
Chapter 12.Toxicologic Properties of 2'-0-
Methoxyethyl Chimeric Antisense Inhibitors in
Animals and Man .................................... 327
Scott P. Henry, Tae-Won Kim, Kimberly
Kramer-Stickland, Thomas A. Zanardi, Robert
A. Fey, and Arthur A. Levin
Chapter 13.An Overview of the Clinical Safety
Experience of First- and Second-Generation
Antisense Oligonucleotides ......................... 365
T. Jesse Kwoh
Chapter 14.Manufacturing and Analytical Processes
for 2'-0-(2-Methoxyethyl)-Modified
Oligonucleotides ................................... 401
Daniel C. Capaldi and Anthony N. Scozzari
Part III В. Hybridization-Based Drugs: Basic Properties
Duplex RNA Drugs .................................. 435
Chapter 15.Utilizing Chemistry to Harness RNA
Interference Pathways for Therapeutics:
Chemically Modified siRNAs and Antagomirs .......... 437
Muthiah Manoharan and Kallanthottathil
G. Rajeev
Chapter 16.Discovery and Development of RNAi
Therapeutics ....................................... 465
Antonin R. de Fougerolles and John
M. Maraganore
Part IV. Other Chemical Classes of Drugs ...................... 485
Chapter 17.Optimization of Second-Generation Antisense
Drugs: Going Beyond Generation 2.0 ................. 487
Brett P. Monia, Rosie Z. Yu, Walt Lima,
and Andrew Siwkowski
Chapter 18.Modulating Gene Function with Peptide Nucleic
Acids (PNA) ........................................ 507
Peter E. Nielsen
Chapter 19.Locked Nucleic Acid ................................ 519
Troels Koch and Henrik 0rum
Chapter 20.Morpholinos ........................................ 565
Patrick L. Iversen
Part V Therapeutic Applications ............................... 583
Chapter 21.Potential Therapeutic Applications of
Antisense Oligonucleotides in Ophthalmology ........ 585
Lisa R. Grillone and Scott P. Henry
Chapter 22.Cardiovascular Therapeutic Applications ............ 601
Rosanne Crooke, Brenda Baker, and Mark Wedel
Chapter 23.Developing Antisense Drugs for Metabolic
Diseases: A Novel Therapeutic Approach ............. 641
Sanjay Bhanot
Chapter 24.Inflammatory Diseases .............................. 665
Susan A. Gregory and James G. Karras
Chapter 25.Antisense Oligonucleotides for the Treatment of
Cancer ............................................. 699
Boris A. Hadaschik and Martin E. Gleave
Chapter 26.Targeting Neurological Disorders with
Antisense Oligonucleotides ......................... 721
Richard A. Smith and Timothy M. Miller
Chapter 27.Mechanisms and Therapeutic Applications
of Immune Modulatory Oligodeoxynucleotide and
Oligoribonucleotide Ligands for Toll-Like
Receptors .......................................... 747
Jorg Vollmer and Arthur M. Krieg
Chapter 28.Aptamer Opportunities and Challenges ............... 773
Charles Wilson
Index ......................................................... 801
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