Enhanced delivery of peptide-morpholino oligonucleotides with a small molecule to correct splicing defects in the lung.

Autor:	Dang Y; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., van Heusden C; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., Nickerson V; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., Chung F; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., Wang Y; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., Quinney NL; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., Gentzsch M; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., Randell SH; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA., Moulton HM; Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA., Kole R; Department of Pharmacology, The University of North Carolina at Chapel Hill, 4010 Genetic Medicine Bldg, Chapel Hill, NC 27599, USA., Ni A; Initos Pharmaceuticals, LLC, Chapel Hill, NC 27514, USA., Juliano RL; Initos Pharmaceuticals, LLC, Chapel Hill, NC 27514, USA., Kreda SM; Marsico Lung Institute/Cystic Fibrosis Center, The University of North Carolina at Chapel Hill, 6009 Thurston Bowles Bldg, Chapel Hill NC 27599-7248, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2021 Jun 21; Vol. 49 (11), pp. 6100-6113.
DOI:	10.1093/nar/gkab488
Abstrakt:	Pulmonary diseases offer many targets for oligonucleotide therapeutics. However, effective delivery of oligonucleotides to the lung is challenging. For example, splicing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect a significant cohort of Cystic Fibrosis (CF) patients. These individuals could potentially benefit from treatment with splice switching oligonucleotides (SSOs) that can modulate splicing of CFTR and restore its activity. However, previous studies in cell culture used oligonucleotide transfection methods that cannot be safely translated in vivo. In this report, we demonstrate effective correction of a splicing mutation in the lung of a mouse model using SSOs. Moreover, we also demonstrate effective correction of a CFTR splicing mutation in a pre-clinical CF patient-derived cell model. We utilized a highly effective delivery strategy for oligonucleotides by combining peptide-morpholino (PPMO) SSOs with small molecules termed OECs. PPMOs distribute broadly into the lung and other tissues while OECs potentiate the effects of oligonucleotides by releasing them from endosomal entrapment. The combined PPMO plus OEC approach proved to be effective both in CF patient cells and in vivo in the mouse lung and thus may offer a path to the development of novel therapeutics for splicing mutations in CF and other lung diseases. (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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