Antisense Therapeutics by Sudhir Agrawal

By Sudhir Agrawal

Major researchers supply an authoritative survey and research of the newest findings at the fast improvement of antisense oligonucleotides healing and their program in a number of in vivo version platforms. The book's high-profile individuals supply well timed debts in their state of the art suggestions, discussing such issues because the synthesis and purification of oligonucleotides, their choice for a specific gene objective, various tools of management, and using a variety of phone traces and mobilephone tradition structures. in addition they research questions of mobile uptake, in vitro organic task, in vivo organic job, the pharmacology and pharmacokinetics of oligonucleotides, and the applying of oligonucleotides to the primary apprehensive approach.

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Therefore, we turned next to the direct mlection of ODN mto brain parenchyma itself (the caudate nucleus). These studies again demonstrated the presence of significant nuclease activity, and even some degradation of phosphorothioate ODN was observed. However, when phosphorothroate ODN were used, we were struck by the high and circumscribed level of material achieved in the immediate vicinity of the mfusion site, even after several days of contmuous delivery. , unpublished observations). When equal amountsof fluorescent brain extract from phosphodiester and phosphorothioate mfusates were examined by gel electrophorests, little intact phosphodiester material was found, whereas the phosphorothioate ODN extracted was only partially degraded.

There is substantial scope for improvement through medicinal chemistry, and many laboratories have demonstrated that novel antisense oligonucleotide ana- An tisense Therapeubcs 41 logs can have improved properties (reviewed in refs. 82,83). In this chapter, we have described early experiments that demonstrate that improved analogs are more stable and more potent in ammals. Although much remains to be learned, a great deal of progress has clearly been made in an area that 1sproving to be an important advance m therapeutics.

And Yu, Z P (1991) Antisense inhibition of ras p21 expression that is sensitive to a point mutation Biochemrstry 30, 8283-8286. 33 Georges, R. , and Saison-Behmoaras, T (1994) Anttsense oligonucleotides adsorbed to polyalkylcyanoacrylate nanoparticles specifically inhibit mutated Ha-ras-mediated cell prohferatton and tumorigetuclty m nude mice. Proc Nat1 Acad Scr USA 91, 10,460-l 0,464 35. Nishizuka, Y. (1992) Intracellular signaling by hydrolysis of phosphohprds and activation of protein kinase C Science 258,607-614.

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