A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice
Antisense RNA technology is a strategy for the treatment of Duchenne muscular dystrophy (DMD), a progressive and universally fatal X-linked neuromuscular disease caused by frameshift mutations in the gene encoding dystrophin. Phosphorodiamidate morpholino oligomers (PMOs) are an antisense RNA platfo...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253122002189 |
| _version_ | 1818049666393047040 |
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| author | Li Gan Leslie C.L. Wu Jenna A. Wood Monica Yao Chris M. Treleaven Nelsa L. Estrella Bruce M. Wentworth Gunnar J. Hanson Marco A. Passini |
| author_facet | Li Gan Leslie C.L. Wu Jenna A. Wood Monica Yao Chris M. Treleaven Nelsa L. Estrella Bruce M. Wentworth Gunnar J. Hanson Marco A. Passini |
| author_sort | Li Gan |
| collection | DOAJ |
| description | Antisense RNA technology is a strategy for the treatment of Duchenne muscular dystrophy (DMD), a progressive and universally fatal X-linked neuromuscular disease caused by frameshift mutations in the gene encoding dystrophin. Phosphorodiamidate morpholino oligomers (PMOs) are an antisense RNA platform that is used clinically in patients with DMD to facilitate exon skipping and production of an internally truncated, yet functional, dystrophin protein. Peptide-conjugated PMOs (PPMOs) are a next-generation platform in which a cell-penetrating peptide is conjugated to the PMO backbone, with the goal of increasing cellular uptake. RC-1001 is a PPMO that contains a proprietary cell-penetrating peptide and targets the Dmd mutation in mdx mice. It was evaluated in mdx mice for exon 23 skipping, dystrophin production, and functional efficacy. Single-dose RC-1001 dose dependently increased exon skipping and dystrophin protein levels in striated muscle and is associated with improvements in muscle function. Dystrophin protein levels were durable for 60 days. Three doses, each given 1 month apart, increased exon skipping to 99% in quadriceps and 43% in heart, with dystrophin protein levels at 39% and 9% of wild type, respectively. These findings support clinical development of PPMO therapies for the treatment of DMD. |
| first_indexed | 2024-12-10T10:41:12Z |
| format | Article |
| id | doaj.art-bddb1e4b922e426fa81d57fe314dc534 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-10T10:41:12Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-bddb1e4b922e426fa81d57fe314dc5342022-12-22T01:52:18ZengElsevierMolecular Therapy: Nucleic Acids2162-25312022-12-01301727A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx miceLi Gan0Leslie C.L. Wu1Jenna A. Wood2Monica Yao3Chris M. Treleaven4Nelsa L. Estrella5Bruce M. Wentworth6Gunnar J. Hanson7Marco A. Passini8Sarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USASarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USASarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USA; Corresponding author Jenna A. Wood, Sarepta Therapeutics, Inc. 215 First Street Cambridge, MA 02142, USA.Sarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USASarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USASarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USASarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USASarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USASarepta Therapeutics, Inc., 215 First Street Cambridge, Cambridge, MA 02142, USAAntisense RNA technology is a strategy for the treatment of Duchenne muscular dystrophy (DMD), a progressive and universally fatal X-linked neuromuscular disease caused by frameshift mutations in the gene encoding dystrophin. Phosphorodiamidate morpholino oligomers (PMOs) are an antisense RNA platform that is used clinically in patients with DMD to facilitate exon skipping and production of an internally truncated, yet functional, dystrophin protein. Peptide-conjugated PMOs (PPMOs) are a next-generation platform in which a cell-penetrating peptide is conjugated to the PMO backbone, with the goal of increasing cellular uptake. RC-1001 is a PPMO that contains a proprietary cell-penetrating peptide and targets the Dmd mutation in mdx mice. It was evaluated in mdx mice for exon 23 skipping, dystrophin production, and functional efficacy. Single-dose RC-1001 dose dependently increased exon skipping and dystrophin protein levels in striated muscle and is associated with improvements in muscle function. Dystrophin protein levels were durable for 60 days. Three doses, each given 1 month apart, increased exon skipping to 99% in quadriceps and 43% in heart, with dystrophin protein levels at 39% and 9% of wild type, respectively. These findings support clinical development of PPMO therapies for the treatment of DMD.http://www.sciencedirect.com/science/article/pii/S2162253122002189MT: oligonucleotides: therapies and applicationsDuchenne muscular dystrophydystrophinexon-skipping therapyneuromuscular diseasepeptide-conjugated phosphorodiamidate morpholino oligomer |
| spellingShingle | Li Gan Leslie C.L. Wu Jenna A. Wood Monica Yao Chris M. Treleaven Nelsa L. Estrella Bruce M. Wentworth Gunnar J. Hanson Marco A. Passini A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice Molecular Therapy: Nucleic Acids MT: oligonucleotides: therapies and applications Duchenne muscular dystrophy dystrophin exon-skipping therapy neuromuscular disease peptide-conjugated phosphorodiamidate morpholino oligomer |
| title | A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice |
| title_full | A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice |
| title_fullStr | A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice |
| title_full_unstemmed | A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice |
| title_short | A cell-penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice |
| title_sort | cell penetrating peptide enhances delivery and efficacy of phosphorodiamidate morpholino oligomers in mdx mice |
| topic | MT: oligonucleotides: therapies and applications Duchenne muscular dystrophy dystrophin exon-skipping therapy neuromuscular disease peptide-conjugated phosphorodiamidate morpholino oligomer |
| url | http://www.sciencedirect.com/science/article/pii/S2162253122002189 |
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