1 Mechanisms of Oligonucleotide Actions 1
2 The Medicinal Chemistry of Antisense Oligonucleotides 39
3 Cellular Pharmacology of Antisense Oligonucleotides 91
4 Pharmacokinetics and Pharmacodynamics of Antisense Oligonucleotides 107
5 Tissue Distribution, Metabolism, and Clearance 137
6 Hybridization-Independent Effects: Principles and Specific Considerations for Oligonucleotide Drugs 161
7 Hybridization-Dependent Effects: The Prediction, Evaluation,and Consequences of Unintended Target Hybridization 191
8 Class-Related Proinflammatory Effects 227
9 Exaggerated Pharmacology 243
10 Genotoxicity Tests for Novel Oligonucleotide-Based Therapeutics 257
11 Reproductive and Developmental Toxicity Testing Strategies for Oligonucleotide-Based Therapeutics 287
12 Specific Considerations for Preclinical Development of Inhaled Oligonucleotides 311
13 Lessons Learned in Oncology Programs 331
14 Inhaled Antisense for Treatment of Respiratory Disease 355
15 Antisense Oligonucleotides for Treatment of Neurological Diseases 389
16 Nucleic Acids as Adjuvants 411
17 Splice-Switching Oligonucleotides 445
18 CMC Aspects for the Clinical Development of Spiegelmers 491
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.
• 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.