RNA interference: a potential therapeutic tool for silencing splice isoforms linked to human diseases

Abstract

Alternative splicing of precursor messenger RNAs (pre-mRNAs) is one of the most important sources of protein diversity in vertebrates. An estimated 35%–70% of human genes generate transcripts that are alternatively spliced, and defects in this process are linked to numerous human genetic diseases and various forms of cancer. The discovery that 21–23 nucleotide RNA duplexes, known as small interfering RNAs (siRNAs), can knockdown the homologous mRNAs in mammalian cells has revolutionized many aspects of drug discovery including down-regulation of disease-associated splicing isoforms. In addition, RNA interference (RNAi)-mediated silencing of splicing regulators has the potential to define the complex network of alternative splicing regulation and to analyze gene function. In this review, I first provide a brief introduction to mRNA splicing and its relationship to human diseases. This is followed by a brief overview of RNAi. Finally I discuss the therapeutic potential of RNAi in targeting disease-linked splicing isoforms.