Ciba Foundation Symposium 209 ‐ Oligonucleotides as Therapeutic Agents: Oligonucleotides as Therapeutic Agents: Ciba Foundation Symposium 209

The use of oligonucleotides as therapeutic agents rests upon their ability to interfere, in a sequence-specific manner, with the fundamental machinery of protein synthesis either by binding to the mRNAs transcribed from a gene or by binding directly to a target gene. This approach can be used not only for inhibition of the synthesis of host proteins but also of those required by invading pathogens. Potential therapeutic applications are enormous, ranging over hypertension, cardiovascular disease, autoimmune disease, vital and other parasitic infections (especially HIV), and cancer. This book discusses the chemistry and pharmacokinetics of oligonucleotides and their analogues, and surveys the results of structure-activity studies and current clinical trials. It also critically reviews the problems with antisense therapy, such as the enzymatic destruction of oligonucleotides, the doses required for a therapeutic response, the difficulty in directing oligonucleotides to particular target tissues and cells, the need for parenteral administration, and doubts concerning the mechanism of action (especially problems associated with non-specific binding to proteins) and long-term effects. Content: Oligoncleotide Analogues : An Overview / Mark Matteucci -- Phosphorothioate Oligodeoxynucleotides : Large-scale Synthesis And Analysis, Impurity Characterization, And The Effects Of Phosphorus Stereochemistry / Karen L. Fearon, Bernard L. Hirschbein, Choi-ying Chiu, Maria R. Quijano And Gerald Zon -- Discovering Antisense Reagents By Hybridization Of Rna To Oligonucleotide Arrays / E.m. Southern, N. Milner And K.u. Mir -- Pharmacokinetics Of Oligonucleotides In Cell Culture / Bernard Lebleu, Ian Robbins, Lionel Bastide, Eric Vives And Jay E. Gee -- Pharmacokinetics Of Oligonucleotides / Sudhir Agrawal And Ruiwen Zhang -- Controversies In The Cellular Pharmacology Of Oligodeoxynucleotides / C.a. Stein -- Sequence-specific Control Of Gene Expression By Antigene And Clamp Oligonucleotides / Claude Hélène, Carine Giovannangeli, Anne-laure Guieysse-peugeot And Danièle Praseuth -- First- And Second-generation Antisense Oligonucleotide Inhibitors Targeted Against Human C-raf Kinase / Brett P. Monia -- Differential Oligonucleotide Activity In Cell Culture Versus Mouse Models / Eric Wickstrom And Frederick L. Tyson -- Structure-activity Relationships In Cell Culture / Richard W. Wagner -- Progress In Antisense Therapeutics Discovery And Development / Stanley T. Crooke -- Oligonucleotide Therapeutics For Human Leukaemia / Alan M. Gewirtz -- Therapeutic Applications Of Catalytic Antisense Rnas (ribozymes) / John J. Rossi -- Exogenous Application Of Ribozymes For Inhibiting Gene Expression / Fritz Eckstein -- Efficient Process Technologies For The Preparation Of Oligonucleotides / Wolfgang Pieken -- In Vivo Production Of Oligodeoxyribonucleotides Of Specific Sequences : Application To Antisense Dna / Masayori Inouye, Jau-ren Mao, Tadashi Shimamoto And Sumiko Inouye. [editors, Derek J. Chadwick (organizer) And Gail Cardew]. Includes Index. Proceedings Of The Symposium On Oligonucleotides As Therapeutic Agents, Held At Ciba Foundation On 7-9 January 1997. Includes Bibliographical References And Indexes.