Advances in therapeutic RNA-targeting.

This paper reviews the advances in the past decade of different applications of modulating the level and content of mRNA by antisense oligonucleotide (AON)-based exon skipping. The primary aim of such modulation is the correction of genetic defects by alteration of the resulting protein such that the dysfunction is reduced or relieved. This application is in several clinical phase III trails, notably for Duchenne muscular dystrophy and earlier clinical trials are in preparation for other diseases, a.o. spinal muscular atrophy. An alternative aim may be to disrupt the reading frame of dysfunctional proteins when they have a dominant negative effect and their absence may ameliorate disease. A third aim is to target mRNAs for other proteins, the engineering of which might improve or prevent the disease. A final application, which is as yet under-explored but has major promise, is the functional in vivo study of protein isoforms by modulating their relative levels by AON-based skipping of alternative exons.