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Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle wasting disorder caused by reading frame disrupting mutations in the DMD gene. Exon skipping is a therapeutic approach for DMD. It employs antisense oligonucleotides (AONs) to restore the disrupted open reading frame, allowing the pro...

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Autores principales: Jirka, Silvana M.G., ’t Hoen, Peter A.C., Diaz Parillas, Valeriano, Tanganyika-de Winter, Christa L., Verheul, Ruurd C., Aguilera, Begona, de Visser, Peter C., Aartsma-Rus, Annemieke M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763161/
https://www.ncbi.nlm.nih.gov/pubmed/29103911
http://dx.doi.org/10.1016/j.ymthe.2017.10.004
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author Jirka, Silvana M.G.
’t Hoen, Peter A.C.
Diaz Parillas, Valeriano
Tanganyika-de Winter, Christa L.
Verheul, Ruurd C.
Aguilera, Begona
de Visser, Peter C.
Aartsma-Rus, Annemieke M.
author_facet Jirka, Silvana M.G.
’t Hoen, Peter A.C.
Diaz Parillas, Valeriano
Tanganyika-de Winter, Christa L.
Verheul, Ruurd C.
Aguilera, Begona
de Visser, Peter C.
Aartsma-Rus, Annemieke M.
author_sort Jirka, Silvana M.G.
collection PubMed
description Duchenne muscular dystrophy (DMD) is a severe, progressive muscle wasting disorder caused by reading frame disrupting mutations in the DMD gene. Exon skipping is a therapeutic approach for DMD. It employs antisense oligonucleotides (AONs) to restore the disrupted open reading frame, allowing the production of shorter, but partly functional dystrophin protein as seen in less severely affected Becker muscular dystrophy patients. To be effective, AONs need to be delivered and effectively taken up by the target cells, which can be accomplished by the conjugation of tissue-homing peptides. We performed phage display screens using a cyclic peptide library combined with next generation sequencing analyses to identify candidate muscle-homing peptides. Conjugation of the lead peptide to 2′-O-methyl phosphorothioate AONs enabled a significant, 2-fold increase in delivery and exon skipping in all analyzed skeletal and cardiac muscle of mdx mice and appeared well tolerated. While selected as a muscle-homing peptide, uptake was increased in liver and kidney as well. The homing capacity of the peptide may have been overruled by the natural biodistribution of the AON. Nonetheless, our results suggest that the identified peptide has the potential to facilitate delivery of AONs and perhaps other compounds to skeletal and cardiac muscle.
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spelling pubmed-57631612019-01-03 Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy Jirka, Silvana M.G. ’t Hoen, Peter A.C. Diaz Parillas, Valeriano Tanganyika-de Winter, Christa L. Verheul, Ruurd C. Aguilera, Begona de Visser, Peter C. Aartsma-Rus, Annemieke M. Mol Ther Original Article Duchenne muscular dystrophy (DMD) is a severe, progressive muscle wasting disorder caused by reading frame disrupting mutations in the DMD gene. Exon skipping is a therapeutic approach for DMD. It employs antisense oligonucleotides (AONs) to restore the disrupted open reading frame, allowing the production of shorter, but partly functional dystrophin protein as seen in less severely affected Becker muscular dystrophy patients. To be effective, AONs need to be delivered and effectively taken up by the target cells, which can be accomplished by the conjugation of tissue-homing peptides. We performed phage display screens using a cyclic peptide library combined with next generation sequencing analyses to identify candidate muscle-homing peptides. Conjugation of the lead peptide to 2′-O-methyl phosphorothioate AONs enabled a significant, 2-fold increase in delivery and exon skipping in all analyzed skeletal and cardiac muscle of mdx mice and appeared well tolerated. While selected as a muscle-homing peptide, uptake was increased in liver and kidney as well. The homing capacity of the peptide may have been overruled by the natural biodistribution of the AON. Nonetheless, our results suggest that the identified peptide has the potential to facilitate delivery of AONs and perhaps other compounds to skeletal and cardiac muscle. American Society of Gene & Cell Therapy 2018-01-03 2017-10-12 /pmc/articles/PMC5763161/ /pubmed/29103911 http://dx.doi.org/10.1016/j.ymthe.2017.10.004 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Jirka, Silvana M.G.
’t Hoen, Peter A.C.
Diaz Parillas, Valeriano
Tanganyika-de Winter, Christa L.
Verheul, Ruurd C.
Aguilera, Begona
de Visser, Peter C.
Aartsma-Rus, Annemieke M.
Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
title Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
title_full Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
title_fullStr Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
title_full_unstemmed Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
title_short Cyclic Peptides to Improve Delivery and Exon Skipping of Antisense Oligonucleotides in a Mouse Model for Duchenne Muscular Dystrophy
title_sort cyclic peptides to improve delivery and exon skipping of antisense oligonucleotides in a mouse model for duchenne muscular dystrophy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763161/
https://www.ncbi.nlm.nih.gov/pubmed/29103911
http://dx.doi.org/10.1016/j.ymthe.2017.10.004
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