chapter  4
26 Pages

Splice Switching Oligonucleotides as Potential Therapeutics

WithPeter Sazani, Maria A. Graziewicz, Ryszard Kole

Antisense oligonucleotides (AONs) are typically applied as targeted downregulators of mRNA translation. This action is achieved by base pairing of specific 2-deoxyoligonucleotides with the targeted mRNA, a process that elicits destruction of the mRNA by RNase H, an enzyme that catalyzes RNA breakdown in an RNA/DNA duplex [12]. In recent years, the manipulation of splicing has been accomplished with chemically modified AONs that do not activate RNase H, thereby redirecting aberrant or alternative splicing rather than causing destruction of the targeted pre-mRNA, thus upregulating the synthesis of correct and/or therapeutic gene products. Benefits of such approach include possible use as a method to determine function of gene isoforms, positive readout assay for antisense activity, and most importantly, therapeutic potential for genetic diseases and a variety of other disorders that can be addressed by manipulation of alternative splicing of specific genes. In this chapter we will review pertinent literature since 2001, the time of publication of the previous edition of this volume, to present.