SEBASTIEN DESHAYES, GILLES DIVITA
University of Montpellier Centre de Recherches de Biochimie Macromoléculaire, CRBM-CNRS, UMR-5237, UM1-UM2, Chemical Biologyand Nanotechnology for Therapeutics, 1919 Route de Mende, 34293 Montpellier, France

Abstract

Personalized medicine approaches based on different gene therapy settings have gained much attention lately. In order to enforce successful gene therapy, genetic material needs to be delivered into cells. Nucleic acids and their analogues are unable to do so and thus require assistance to reach their site of action residing in the cytoplasm or nucleus. Here we give a short review on recent advancements in cell-penetrating peptide mediated delivery of splice-correcting oligonucleotides. We report on different cell-penetrating peptides applied for vectorization of splice-correcting oligonucleotides using both covalent conjugation and non-covalent nanoparticle formation approach. While covalent conjugation has gained extensive interest, there have also been great advances in non-covalent complex formation.

INTRODUCTION 

Although, major progress has been made on different aspects of RNAi technology, including chemistry and delivery, the major obstacle to siRNA clinical development remains their low cellular uptake associated with a poor in vivo stability and a lack of efficient and specific delivery systems (1-3).The low bioavailability and the poor cellular uptake associated with the lack of permeability of the cell membrane to negatively charged nucleic acids constitute the main limitations of the success of siRNA-based therapy (2-4). Therefore, the success of siRNA therapy is highly dependent on the design of suitable delivery systems that can protect siRNA from degradation and specifically deliver it to target cells. (5,6). Numerous viral and non-viral strategies have been proposed to improve the delivery of synthetic small oligonucleotides both in cultured cells and in vivo (4-7). Among these different strategies, Cell-Penetrating Peptides (CPPs) constitute a very promising approach opening new perspectives for drug delivery (8-10). CPPs are usually short peptides of less than 30 amino acids, able to cross cell membranes with different mechanism which ...