PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation

Kariem Ezzat*, Samir El Andaloussi, Eman M. Zaghloul, Taavi Lehto, Staffan Lindberg, Pedro M.D. Moreno, Joana R. Viola, Tarek Magdy, Rania Abdo, Peter Guterstam, Rannar Sillard, Suzan M. Hammond, Matthew J.A. Wood, Andrey A. Arzumanov, Michael J. Gait, C. I.Edvard Smith, Mattias Hällbrink, Ülo Langel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)5284-5298
Number of pages15
JournalNucleic acids research
Volume39
Issue number12
DOIs
StatePublished - Jul 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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