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Numerous human genetic diseases are caused by mutations that give rise to aberrant alternative splicing. Recently, several of these debilitating disorders have been shown to be amenable for splice-correcting oligonucleotides (SCOs) that modify splicing patterns and restore the phenotype in experimental models. However, translational approaches are required to transform SCOs into usable drug products. In this study, we present a new cell-penetrating peptide, PepFect14 (PF14), which efficiently delivers SCOs to different cell models including HeLa pLuc705 and mdx mouse myotubes; a cell culture model of Duchenne's muscular dystrophy (DMD). Non-covalent PF14-SCO nanocomplexes induce splice-correction at rates higher than the commercially available lipid-based vector Lipofectamine 2000 (LF2000) and remain active in the presence of serum. Furthermore, we demonstrate the feasibility of incorporating this delivery system into solid formulations that could be suitable for several therapeutic applications. Solid dispersion technique is utilized and the formed solid formulations are as active as the freshly prepared nanocomplexes in solution even when stored at an elevated temperatures for several weeks. In contrast, LF2000 drastically loses activity after being subjected to same procedure. This shows that using PF14 is a very promising translational approach for the delivery of SCOs in different pharmaceutical forms.

Original publication

DOI

10.1093/nar/gkr072

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

07/2011

Volume

39

Pages

5284 - 5298

Keywords

Alternative Splicing, Animals, Cell-Penetrating Peptides, Cells, Cultured, Culture Media, Culture Media, Serum-Free, Endocytosis, HeLa Cells, Humans, Kinetics, Light, Lipopeptides, Mice, Muscle Fibers, Skeletal, Nanostructures, Oligonucleotides, Antisense, Scattering, Radiation, Solutions, Temperature