Stanley T. Crooke - Böcker

Extensively revised and updated, Antisense Drug Technology: Principles, Strategies, and Applications, Second Edition reflects the logarithmic progress made in the past four years of oligonucleotide-based therapies, and, in particular, antisense therapeutics and research. Interpreting lessons learned from the clinical trials of first generation drugs, the book evaluates the technology as a whole and offers new directions and avenues of research and development.Divided into five parts, the book begins with a thorough introduction to the mechanism of antisense drug action including the RNase H mechanism, small RNA silencing pathways, and the potential therapeutics of splice switching oligonucleotides. Leading researchers demonstrate the basics of oligonucleotide therapeutics in part two by delineating medicinal chemistry, pharmacokinetics, and delivery routes such as liposomal formulations for nucleic acid delivery. Part three details hybridization based drugs and considers the dramatic advances represented by 2’ methoxyethyl chimeric antisense inhibitors and duplex RNA drugs. Other chemical classes of drugs and mechanisms of action are described in part four with further discussions on improving the second generation antisense drugs. The final part delves deeply into therapeutic applications. Contributing authors examine the potential of antisense drugs for the alleviation of cardiovascular diseases, metabolic diseases, inflammatory diseases, cancer, neurological disorders, and immune modulation. Presenting a highly detailed, lucid discussion of the remarkable advances in the field, Antisense Drug Technology: Principles, Strategies, and Applications, Second Edition provides the platform for researchers to continue to aggressively pursue the great opportunity represented by this exciting technology.

The heat-shock proteins in E. coli are transiently overexpressed af- ter shift to a higher growth temperature. The genes that encode the HSPs are preceded by promoters transcribed in vitro by a form of RNA poly- 32 32 merase holoenzyme containing a 32-kd a subunit (Ea ). The a subunit is encoded by the rpoH (htpR) gene, previously identified as a positive 32 effector of the heat-shock response. Our evidence suggests that Ea is the enzyme that transcribes heat-shock genes at all temperatures. The level 32 of a may be regulated at several points: Accumulation of rpoH mRNA 32 is affected by temperature shift, a synthesis is regulated posttranscrip- 32 tionally, and a is an unstable molecule with a tl/2 of 5 min. Many mu- tations in the HSPs are shown to have defects in proteolysis. References Baker. T. A. , Grossman. A. D . . and Gross. C. A. , 1984, A gene regulating the heat shock response in Escherichia coli also affects proteolysis. Proc. Natl. A cad. Sci. US. A. 81:6779-6783. Bardwell, J. C. A . . and Craig, E. A . . 1984. Major heat shock gene of Drosophila and the Escherichia coli heat-inducible dnaK gene are homologous, Proc. Natl. Acad. Sci. US. A. 81:848-852. Bukhari. A. I. .and Zipser. D . . 1973, Mutants of Escherichia coli with a defect in the degradation of nonsense fragments, Nature New Bioi. 243:238-241. Charette. M. F. , Henderson, G. W. , and Markovitz, A.

It is less than 80 years since John Newport Langley first proposed the role of "receptive substances" as the site of drug action from his obser­ vations on the effects of nicotine and curare at the myoneural junction. The many advances in our understanding of receptor biology that have occurred during the intervening period mirror the extraordinary growth of knowledge in the biological sciences and in cell and molecular biology in particular. Receptor biology, in common with many other topics in contemporary biology, is on the threshold of a transition from being a descriptive, phenomenological discipline to one in which underlying mechanisms and regulatory principles can be defined with increasing pre­ cision. This change, together with the evolution of powerful analytical techniques and timely convergence of ideas from a number of previously separate fields of inquiry, is generating an increasingly unified theoretical and experimental framework for the study of receptor function. These themes, and the mood of anticipation that a real understanding of receptor function in health and disease is emerging, are reflected in in this volume, which summarizes the proceedings of the Sec­ the papers ond Smith Kline & French Research Symposium on New Horizons in Therapeutics held in Philadelphia in 1984.

The characterization of the cellular and molecular mechanisms that mediate inflammation provides a foundation that supports future studies that will de­ fine mechanisms more intimately. It encourages substantial optimism about the opportunities to understand the inflammatory process and to use that information to develop novel therapeutic approaches. Recent progress has defined the cells that mediate the inflammatory response, many of the inter­ cellular transmitters, the receptors, signal transduction processes and regula­ tory mechanisms. Thus, we now have the opportunity to understand inflammation in pharmacologic terms and to attack the key molecular targets to develop new therapeutics. Among the cells involved in the inflammatory response are the lympho­ cytes, neutrophils and endothelial cells. Maintenance of homeostasis, re­ sponse to proinflammatory stimuli and pathophysiologic responses are products of complex interactions between these and other elements of the immune systems. Each of these cells displays a variety of receptors to define the stimuli to which they respond. The receptors displayed that the signal transduction processes and cellular responses are regulated genetically and epigenetic ally . The critical role of membranes and particularly the phospho­ lipid components of the membranes is emphasized by recent studies.

Dopamine, in addition to its importance as a precursor of norepinephrine, is now known to be an important neurotransmitter in regulating functional activities in a number of major organ systems, including the central ner­ vous system. the cardiovascular system, the kidney, and the gut. Recent advances in our understanding of the functional role of dopamine, its mechanism of action and the pharmacology of dopaminergic agents have occurred on a broad front. The last few years have witnessed significant progress in the identification and classification of central and peripheral dopamine receptors and the factors that affect their responsiveness to inhibitory and stimulatory ligands. These advances have been paralleled by new insights into the contribution of alterations in dopaminergic reg­ ulation in causing disease and the utility of dopamine agonists and an­ tagonists as therapeutic modalities. This volume, the first in a series of publications arising from the annual Smith Kline and French Research Symposium on New Horizons in Therapeutics, provides a comprehensive survey of current research on peripheral dopamine receptors and the physiologic and therapeutic con­ sequences of stimulating pre-and postsynaptic dopamine receptors. Research in dopamine pharmacology mirrors the remarkable ad­ vances that are occurring in the field of pharmacology at large as a con­ sequence of the involvement of an ever-larger number of scientific dis­ ciplines in the study of drug action.

Antisense technology may result in dramatic changes in the therapy of many diseases and may provide tools to dissect pharmacological processes and to confirm the roles of various genes. In this volume, progress in the understanding of antisense technology and its use in creating new drugs is discussed. Potential caveats, pitfalls and limitations of the technology are also presented. In the next few years the pace at which new molecular targets will be identified will increase exponentially as the sequencing of the human genome and of other genomes proceeds.