Oligonucleotide therapy

Oligonucleotides (ONs), the focus of the chapter herein, are mostly known for their utility to selectively manipulate RNA processing by increasing or decreasing target gene levels, in particular by inducing enzymatic RNA degradation, blocking or mimicking miRNAs, inhibiting mRNA translation or modulating pre-mRNA splicing. Since these mechanisms of action are based on the Watson–Crick base pairing to target sequences, ONs are highly specific compounds. The possibility of a large scale and standardized production of these compounds makes them attractive for the therapy of inherited disorders. To date, four ONs have received marketing authorization and more than 100 have been, or are, under clinical trials. Several different oligonucleotide chemistries have been explored, each with its own delivery hurdles and toxicology patterns. Only a limited knowledge is available concerning the cellular and subcellular mechanisms of ONs uptake, transport and metabolism, presently making the improvement of ONs’ delivery and toxicology a challenging task. The purpose of this chapter is to review the state-of-the-art advances on ONs for applications in inherited disorders and give an overview of what is known regarding their delivery and safety, based on preclinical and clinical studies.