Strategies for the design and delivery of antisense oligonucleotides in central nervous system.

Publisher Summary Nucleic acid pharmaceuticals are of increasing interest to the health care community because of their almost unlimited potential in the treatment of diseases such as cancer, genetic and degenerative disorders, viral infection, and the molecular pathologic sequelae of trauma or ischemia. Modified antisense oligodeoxynucleotides (oligonucleotides; ODNs) offer the potential to block the expression of specific genes within cells. Such strategies have antiproliferative activity in rapidly dividing cells when directed at appropriate targets and alter cellular interactions and behavior in other ways, depending on the role of the gene product whose expression has been reduced. The advantages of using antisense oligonucleotides include their ease of synthesis, their low molecular weight, the variety of gene targets available, and their potential for both specificity and low toxicity. Unique features of the central nervous system (CNS) render it an area of both opportunity and challenge for the application of antisense ODN strategies. Historically, the powerful ability of the blood–brain barrier to exclude ODNs and their analogs has prevented widespread investigation of this approach. More recently, the compartmentalized nature of the CNS, coupled with innovative delivery techniques, has rekindled interest in the application of therapeutic antisense ODN strategies in the CNS. This chapter discusses technical aspects of the efforts to design and test antioncogene strategies for therapeutic application in the treatment of primary intracranial tumors. The applicability of such strategies to other CNS pathologies is also briefly discussed.