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

doi:10.1093/nar/gkr072

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 journal › Article › peer-review

194 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 language	English (US)
Pages (from-to)	5284-5298
Number of pages	15
Journal	Nucleic acids research
Volume	39
Issue number	12
DOIs	https://doi.org/10.1093/nar/gkr072
State	Published - Jul 2011
Externally published	Yes

Funding

Swedish Research Council (VR-NT); VINNOVA-SAMBIO joint project; SSF (Sweden-Japan); Center for Biomembrane Research, Stockholm; Knut and Alice Wallenberg’s Foundation; the EU trough the European Regional Development Fund through the Center of Excellence in Chemical Biology, Estonia; the targeted financing SF0180027s08 from the Estonian Government; the DoRa Program of The European Social Fund; Archimedes Foundation; the Torsten and Ragnar Söderberg Foundation; KI faculty funds for funding of postgraduated students (to J.R.V.); Egyptian Ministry of Higher Education (to E.M.Z.); Swedish Society of Medical Research (SSMF to S.E.A.); Work in the Gait laboratory is supported by the Medical Research Council (Unit program U105178803). Funding for open access charge: Swedish Research Council (VR-NT).

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/nar/gkr072

Cite this

Ezzat, K., El Andaloussi, S., Zaghloul, E. M., Lehto, T., Lindberg, S., Moreno, P. M. D., Viola, J. R., Magdy, T., Abdo, R., Guterstam, P., Sillard, R., Hammond, S. M., Wood, M. J. A., Arzumanov, A. A., Gait, M. J., Smith, C. I. E., Hällbrink, M., & Langel, Ü. (2011). PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation. Nucleic acids research, 39(12), 5284-5298. https://doi.org/10.1093/nar/gkr072

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

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{\texttrademark} 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.",

author = "Kariem Ezzat and {El Andaloussi}, Samir and Zaghloul, {Eman M.} and Taavi Lehto and Staffan Lindberg and Moreno, {Pedro M.D.} and Viola, {Joana R.} and Tarek Magdy and Rania Abdo and Peter Guterstam and Rannar Sillard and Hammond, {Suzan M.} and Wood, {Matthew J.A.} and Arzumanov, {Andrey A.} and Gait, {Michael J.} and Smith, {C. I.Edvard} and Mattias H{\"a}llbrink and {\"U}lo Langel",

note = "Funding Information: Swedish Research Council (VR-NT); VINNOVA-SAMBIO joint project; SSF (Sweden-Japan); Center for Biomembrane Research, Stockholm; Knut and Alice Wallenberg{\textquoteright}s Foundation; the EU trough the European Regional Development Fund through the Center of Excellence in Chemical Biology, Estonia; the targeted financing SF0180027s08 from the Estonian Government; the DoRa Program of The European Social Fund; Archimedes Foundation; the Torsten and Ragnar S{\"o}derberg Foundation; KI faculty funds for funding of postgraduated students (to J.R.V.); Egyptian Ministry of Higher Education (to E.M.Z.); Swedish Society of Medical Research (SSMF to S.E.A.); Work in the Gait laboratory is supported by the Medical Research Council (Unit program U105178803). Funding for open access charge: Swedish Research Council (VR-NT).",

year = "2011",

month = jul,

doi = "10.1093/nar/gkr072",

language = "English (US)",

volume = "39",

pages = "5284--5298",

journal = "Nucleic acids research",

issn = "0305-1048",

publisher = "Oxford University Press",

number = "12",

}

Ezzat, K, El Andaloussi, S, Zaghloul, EM, Lehto, T, Lindberg, S, Moreno, PMD, Viola, JR, Magdy, T, Abdo, R, Guterstam, P, Sillard, R, Hammond, SM, Wood, MJA, Arzumanov, AA, Gait, MJ, Smith, CIE, Hällbrink, M & Langel, Ü 2011, 'PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation', Nucleic acids research, vol. 39, no. 12, pp. 5284-5298. https://doi.org/10.1093/nar/gkr072

TY - JOUR

T1 - PepFect 14, a novel cell-penetrating peptide for oligonucleotide delivery in solution and as solid formulation

AU - Ezzat, Kariem

AU - El Andaloussi, Samir

AU - Zaghloul, Eman M.

AU - Lehto, Taavi

AU - Lindberg, Staffan

AU - Moreno, Pedro M.D.

AU - Viola, Joana R.

AU - Magdy, Tarek

AU - Abdo, Rania

AU - Guterstam, Peter

AU - Sillard, Rannar

AU - Hammond, Suzan M.

AU - Wood, Matthew J.A.

AU - Arzumanov, Andrey A.

AU - Gait, Michael J.

AU - Smith, C. I.Edvard

AU - Hällbrink, Mattias

AU - Langel, Ülo

N1 - Funding Information: Swedish Research Council (VR-NT); VINNOVA-SAMBIO joint project; SSF (Sweden-Japan); Center for Biomembrane Research, Stockholm; Knut and Alice Wallenberg’s Foundation; the EU trough the European Regional Development Fund through the Center of Excellence in Chemical Biology, Estonia; the targeted financing SF0180027s08 from the Estonian Government; the DoRa Program of The European Social Fund; Archimedes Foundation; the Torsten and Ragnar Söderberg Foundation; KI faculty funds for funding of postgraduated students (to J.R.V.); Egyptian Ministry of Higher Education (to E.M.Z.); Swedish Society of Medical Research (SSMF to S.E.A.); Work in the Gait laboratory is supported by the Medical Research Council (Unit program U105178803). Funding for open access charge: Swedish Research Council (VR-NT).

PY - 2011/7

Y1 - 2011/7

N2 - 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.

AB - 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.

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

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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