Foreword

The initial foundation for using either DNA or RNA (oligonucleotides) as therapeutic drugs was formulated by Zamecnik and Stephenson in a classic paper published several years ago (P. C. Zamecnik and M. L. Stephenson, Proc. Natl. Acad. Sci. U. S. A., 1978, 75, 280). Many of us considered that this concept would prove to be a new, refreshing approach for providing revolutionary drugs useful in the treatment of nondruggable diseases. Over time these expectations have been realized as several oligonucleotide drugs (Macugen, Fomivirsen, Mipomersen, Eteplirsen, Nusinersen, Inotersen, and Patisiran) are currently available for treating a diverse group of diseases. There are also a large number of additional oligonucleotides in various stages of drug development.

The path towards identifying drugs in the nucleic acids therapeutic arena has involved many unexpected revelations. Initially the focus was strictly on using antisense oligonucleotides. Over time, new research has opened possibilities for oligonucleotide drugs in such diverse fields as interfering RNA, microRNA, noncoding RNA, splicing modulation of RNA transcripts, targeting toxic repeats in RNA and DNA, investigating RNA and DNA aptamers and ribozymes for treating various disease states, and formulating synthetic agonists of Toll-like receptors. In this book the editors, through various chapters, provide a broad and complete perspective on the history of these fields. As each chapter unfolds, the reader discovers the logic behind why various DNA and RNA analogues were developed, how they were applied in clinical studies, and the limitations and advantages of these analogues. Also clearly presented are details on the unexpected side effects with some of these being very serious, such as the Toll receptor problem, the retention and targeting of oligonucleotides in tissues, and the variation of clinical studies with animal models.

Drug development in the nucleic acids field continues at an increasing rate. Moreover so do the challenges that are important for successfully identifying an oligonucleotide therapeutic drug. This book provides an excellent road map for navigating all that has come before and also outlines for the reader a multitude of possible directions on how to proceed with further research. The editors have assembled an excellent set of authors who are experts in the science as presented in various chapters. This would be expected as both Michael Gait and Sudhir Agrawal are among the most highly respected and experienced research scientists in this field. Thus it is not at all surprising that the science is both current and focused on important concepts. I can enthusiastically recommend this book as both a reference and also as a guide for further research in the nucleic acids therapeutics arena.

Marv Caruthers

University of Colorado