Antisense Drug Technology: Principles, Strategies, and by Stanley T. Crooke PDF

By Stanley T. Crooke

ISBN-10: 0849387957

ISBN-13: 9780849387951

ISBN-10: 0849387965

ISBN-13: 9780849387968

Generally revised and up to date, Antisense Drug expertise: ideas, concepts, and purposes, moment version displays the logarithmic growth made long ago 4 years of oligonucleotide-based treatments, and, particularly, antisense therapeutics and learn. examining classes realized from the scientific trials of first new release medicines, the ebook evaluates the know-how as a complete and gives new instructions and avenues of study and improvement. Divided into 5 components, the publication starts with a radical creation to the mechanism of antisense drug motion together with the RNase H mechanism, small RNA silencing pathways, and the aptitude therapeutics of splice switching oligonucleotides. best researchers show the fundamentals of oligonucleotide therapeutics partly through delineating medicinal chemistry, pharmacokinetics, and supply routes reminiscent of liposomal formulations for nucleic acid delivery.  half 3 information hybridization established medications and considers the dramatic advances represented by means of 2’ methoxyethyl chimeric antisense inhibitors and duplex RNA medications. different chemical periods of substances and mechanisms of motion are defined partially 4 with additional discussions on enhancing the second one iteration antisense medicinal drugs. the ultimate half delves deeply into healing purposes. Contributing authors research the potential for antisense medications for the relief of cardiovascular illnesses, metabolic illnesses, inflammatory ailments, melanoma, neurological issues, and immune modulation. proposing a hugely distinct, lucid dialogue of the impressive advances within the box, Antisense Drug know-how: rules, thoughts, and purposes, moment variation offers the platform for researchers to proceed to aggressively pursue the good chance represented by means of this fascinating expertise.

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Additional info for Antisense Drug Technology: Principles, Strategies, and Applications, Second Edition

Sample text

Clearly, the introduction of a mismatch in the center of a 2Ј gap in a second-generation antisense drug should dramatically reduce activity that would be dependant on RNase H1. It is also possible that editing of siRNA duplexes by adenosine deaminase and editing of single-strand oligoribonucleotides by cytosine deaminase could take place even though they would not be ideal substrates for the enzymes. If that were to happen, of course, off-target effects could ensue. To date, however, no systematic studies of the potential impacts of RNA editing on the activities of antisense drugs have been reported.

Assuming a random distribution of sequences in RNA, any sequence of 13 residues is expected to occur once in the cellular RNA population and, if the nonrandom nature of mammalian RNA sequence is taken into account, an 11-mer or perhaps smaller oligonucleotide could identify and bind to a unique sequence [55]. To exploit fully the theoretical potential for specificity of an oligonucleotide in a therapeutic context, it is necessary to manipulate the length of the oligonucleotide and its concentration at target.

Both in vitro and in vivo, the answer to this question is yes. Analyses of in vitro data are more robust both because there are more data and because differences in pharmacokinetic and toxicologic properties are less likely to influence the results. Activities have been observed for fully modified 2Ј methoxy, 2Ј-MOEs, 4-Lysine and 8-Lysine PNAs, and morpholinos. As a general rule, in vitro potencies correlated with relative affinities for RNA: PNAϾ2Ј-MOEϾϾmorpholinosϾ2Ј methoxy [76–84]. Only modest experience has been reported in vivo.

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Antisense Drug Technology: Principles, Strategies, and Applications, Second Edition by Stanley T. Crooke


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