Peptide-Based Delivery of Steric-Block PNA Oligonucleotides

Several strategies based on synthetic oligonucleotides (ON) have been proposed to control gene expression. As for most biomolecules, however, delivery has remained a major roadblock for in vivo applications. Conjugation of steric-block neutral DNA mimics such as peptide nucleic acids (PNA) or phosphorodiamidate morpholino oligonucleotides (PMO) to cell penetrating peptides (CPP) has recently been proposed as a new delivery strategy. It is particularly suitable to interfere sequence-specifically with pre-mRNA splicing thus offering various applications in fundamental research and in therapeutics. The chemical synthesis of these CPP conjugates as well as methodologies to monitor their cellular uptake and their efficiency in a reliable and easy to implement assay of splicing correction will be described.