Enhancing peptide and PMO delivery to mouse airway epithelia by chemical conjugation with the amphiphilic peptide S10.

Autor:	Auger M; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada.; Département de génie chimique, Faculté des Sciences et de Génie, Université Laval, Pavillon Adrien-Pouliot 1065, av. de la Médecine, Bureau 3550, Québec, QC G1V 0A6, Canada., Sorroza-Martinez L; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada.; Département de génie chimique, Faculté des Sciences et de Génie, Université Laval, Pavillon Adrien-Pouliot 1065, av. de la Médecine, Bureau 3550, Québec, QC G1V 0A6, Canada., Brahiti N; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada., Huppé CA; Centre Collégial de Transfert de Technologie en Biotechnologies TransBIOTech, 201 Rue Monseigneur-Bourget, Lévis, QC G6V 6Z3, Canada., Faucher-Giguère L; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada., Arbi I; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada., Hervault M; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada., Cheng X; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada., Gaillet B; Département de génie chimique, Faculté des Sciences et de Génie, Université Laval, Pavillon Adrien-Pouliot 1065, av. de la Médecine, Bureau 3550, Québec, QC G1V 0A6, Canada., Couture F; Centre Collégial de Transfert de Technologie en Biotechnologies TransBIOTech, 201 Rue Monseigneur-Bourget, Lévis, QC G6V 6Z3, Canada., Guay D; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada.; Département de génie chimique, Faculté des Sciences et de Génie, Université Laval, Pavillon Adrien-Pouliot 1065, av. de la Médecine, Bureau 3550, Québec, QC G1V 0A6, Canada., Soultan AH; Feldan Therapeutics, 2666 Boulevard du Parc Technologique Suite 290, Québec, QC G1P 4S6, Canada.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Jul 31; Vol. 35 (3), pp. 102290. Date of Electronic Publication: 2024 Jul 31 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102290
Abstrakt:	Delivery of antisense oligonucleotides (ASOs) to airway epithelial cells is arduous due to the physiological barriers that protect the lungs and the endosomal entrapment phenomenon, which prevents ASOs from reaching their intracellular targets. Various delivery strategies involving peptide-, lipid-, and polymer-based carriers are being investigated, yet the challenge remains. S10 is a peptide-based delivery agent that enables the intracellular delivery of biomolecules such as GFP, CRISPR-associated nuclease ribonucleoprotein (RNP), base editor RNP, and a fluorescent peptide into lung cells after intranasal or intratracheal administrations to mice, ferrets, and rhesus monkeys. Herein, we demonstrate that covalently attaching S10 to a fluorescently labeled peptide or a functional splice-switching phosphorodiamidate morpholino oligomer improves their intracellular delivery to airway epithelia in mice after a single intranasal instillation. Data reveal a homogeneous delivery from the trachea to the distal region of the lungs, specifically into the cells lining the airway. Quantitative measurements further highlight that conjugation via a disulfide bond through a pegylated (PEG) linker was the most beneficial strategy compared with direct conjugation (without the PEG linker) or conjugation via a permanent thiol-maleimide bond. We believe that S10-based conjugation provides a great strategy to achieve intracellular delivery of peptides and ASOs with therapeutic properties in lungs. Competing Interests: D.G. holds equity in Feldan Therapeutics. N.B., M.A., L.S.M., I.A., L.F.G., X.C., M.H., D.G., and A.H.S. are employees of Feldan Therapeutics. A.H.S. and D.G. have filed patent applications. A.H.S. and D.G. are inventors of a patent related to peptide bioconjugates as delivery agent, and D.G. is also inventor of patents related to peptide-based delivery agents, which are assigned to Feldan Bio Inc. (© 2024 The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu