Preface

Nucleic acids therapeutics are now recognized as the third major drug discovery platform, in addition to small molecules and proteins. In the past three decades, tremendous progress has been made towards the realization of the potential of nucleic acids therapeutics for the treatment of a broad range of diseases. In addition, multiple mechanisms of actions have been elucidated. Recently, several nucleic acid drugs have been approved for clinical use.

Chemical modifications of the three components of nucleic acids – heterocyclic bases, five-membered sugars, and internucleotide linkages – as well as the nucleotide sequences themselves are the key drivers for the creation of nucleic acid drugs. Rational combinations of these have provided drug-like properties. Further advances in the chemistry of nucleic acids and additional insights into their mechanisms of action have expanded their applications to include antisense targeting of mRNA, microRNA, non-coding RNA and splicing modulation, ribozymes, RNA interference (RNAi) and short interfering RNA (siRNA), gene editing, aptamers, and the modulation of immune responses. During the past ten years, since the excellent publication of Jens Kurreck's book (Therapeutic Oligonucleotides), progress in this field has been so rapid and broad that we felt it was appropriate now to document the key developments in the field in the form of a new book.

In Chapter 1 we provide a brief history of the development of nucleotide analogues, early experience in the use of modified antisense oligonucleotides (ONs) from preclinical studies to human trials, as well as the importance of nucleotide sequence and its implications in interaction with innate immune receptors. The next three chapters provide updates on applications of antisense technology. In Chapter 2, David Corey and Zhongtian Liu discuss various mechanisms of action of antisense ONs. In Chapter 3, Eric Swayze and Punit Seth describe the medicinal chemistry of RNase H-activating antisense ONs and in Chapter 4, Richard Geary, Brenda Baker and Brett Monia provide an update on and experience of the application of antisense ONs in clinical development.

During the development of antisense technology, it was realized that subcutaneous delivery of antisense ONs led to activation of host immune responses. Initially, this was thought to be a side effect but soon the discovery of the family of Toll-like receptors (TLRs) led to an understanding of immune activation triggered by receptor-mediated engagement. Tremendous progress has been made in translating these observations into a novel therapeutic platform. In Chapter 13, Shin-Ichiroh Saitoh and Kensuke Miyake provide a detailed background on immune receptors that are known to recognize nucleic acid sequence, patterns, and motifs. In Chapters 5 and 14, one of us (S.A.) and Ekambar Kandimalla have discussed the chemistry of novel nucleic acid compounds and how they modulate receptor-mediated immune responses, along with their therapeutic applications, including clinical proof of concept trials.

A more recent therapeutic application of antisense involves splicing modulation to affect the translation of the targeted pre-mRNA. In Chapter 6, Elena Daoutsali and Annemieke Aartsma-Rus provide an up to date survey on this subject through a variety of examples. Similarly, applications of antisense have been expanded to targeting toxic RNA repeats (Chapter 7 by Derick Wansink and colleagues), microRNA (Chapter 8 by Anna Malinowksi and Jonathan Hall) and long non-coding RNA (Chapter 9 by Claes Wahlestedt and colleagues).

In parallel, significant advances have also been made in RNAi technology for therapeutics. In Chapter 10, Anastasia Khvorova and colleagues discuss in detail the challenges of delivery of RNAi-based therapeutics and how these obstacles have been addressed. In Chapter 11, Muthiah Manoharan and Kallanthottathil Rajeev describe the clinical development of siRNA candidates targeted to liver. In Chapter 12 Jiehua Zhou and John Rossi describe the application of RNAi for treatment of HIV infection. Therapeutic application of ribozyme technology had shown early promise, but has now been found to have significant limitations. In Chapter 18, Darko Balke and Sabine Müller describe novel ribozyme constructs in the search for potential therapeutic applications.

In the past few years, we have also seen explosive growth in the development of gene editing using nucleic acids towards therapeutics. In Chapter 17, Carine Giovannangeli and colleagues provide details on this subject. Synthetic nucleic acids have been studied as aptamers to target proteins and other cellular targets and their clinical evaluation is reviewed in Chapter 15 by Paloma Giangrande and colleagues and in Chapter 16 by Gerald Zon. Through understanding the various mechanisms of actions of nucleic acids, extensive experience has been gained on their safety and pharmacokinetics, both in preclinical and in clinical use. In Chapter 20, Cathaline den Besten and Patrik Andersson discuss this topic in detail and provide their analysis. To maintain successes in the field, significant advances have also been made in manufacturing and quality control, discussed in Chapter 19 by Yogesh Sanghvi.

We are immensely grateful to all these co-authors for their outstanding contributions that provide a detailed story of their respective subjects along with a current bibliography. We are also grateful to the editorial team at the Royal Society of Chemistry (Katie Morrey and Drew Gwilliams, Rowan Frame and Robin Driscoll) for their timely publishing and encouragement and members of the Royal Society of Chemistry staff for their assistance, as well as the many members of the Oligonucleotide Therapeutic Society, the premier professional society in the field, who have contributed to this book, which we hope will become a manual for the state of the art.

In this relatively young field of nucleic acid therapeutics, the use of their sequences to target drugs very precisely in cells and in vivo and the development of nucleic acids chemistry have been paramount and resulted in a substantial broadening of their applications. Rapidly developed and newly approved drugs are now available for the treatment of some rare diseases and other more prevalent diseases are surely following. Despite some setbacks, the list of RNA targets and approved drugs is expanding quickly. We are excited at the future prospects for this field.

Sudhir Agrawal and Michael J. Gait