A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health
Despite the proven safety of dystrophin-targeting phosphorodiamidate morpholino oligomer (PMO) therapy, poor delivery of the PMOs limit the efficacy of this dystrophin restoring gene therapy for Duchenne muscular dystrophy (DMD). Limited myogenesis and excessive fibrosis in DMD are pathological feat...
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| Language: | English |
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Elsevier
2025-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125002197 |
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| author | Young Jae Moon Ravi Hindupur Iteoluwakishi H. Gamu Nikki M. McCormack Fatima Shaikh James S. Novak Jyoti K. Jaiswal |
| author_facet | Young Jae Moon Ravi Hindupur Iteoluwakishi H. Gamu Nikki M. McCormack Fatima Shaikh James S. Novak Jyoti K. Jaiswal |
| author_sort | Young Jae Moon |
| collection | DOAJ |
| description | Despite the proven safety of dystrophin-targeting phosphorodiamidate morpholino oligomer (PMO) therapy, poor delivery of the PMOs limit the efficacy of this dystrophin restoring gene therapy for Duchenne muscular dystrophy (DMD). Limited myogenesis and excessive fibrosis in DMD are pathological features that contribute to the poor efficacy of PMOs. We show that the severe DMD mouse model (D2-mdx) not only replicates these pathological features of DMD but also mirrors the resulting PMO-mediated dystrophin restoration deficit. High transforming growth factor β (TGF-β) activity, which is a common feature of DMD patient and D2-mdx muscles, limits myogenesis and causes fibrosis. We developed a TGF-β-targeting PO (TPMO), which when used acutely, lowered macrophage TGF-β activity and signaling in the dystrophic muscle, enhanced muscle regeneration, and enhanced dystrophin restoration when used in combination with dystrophin exon skipping PMO (DPMO). Chronic use of this combination PMO therapy in D2-mdx mice reduced muscle fibrosis and muscle loss, allowed dystrophin restoration in skeletal muscle and heart, and led to an overall enhancement of skeletal muscle function. This approach leverages the safety of PMO-based therapy and represents the first combination PMO treatment for DMD that simultaneously enhances dystrophin restoration, reduces fibrosis, and alleviates myogenic deficits to ultimately improve health and function of dystrophic muscles. |
| format | Article |
| id | doaj-art-cf8e2ad398bd40b08a4dcc25c4cf1080 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-cf8e2ad398bd40b08a4dcc25c4cf10802025-08-26T04:14:13ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-09-0136310266510.1016/j.omtn.2025.102665A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle healthYoung Jae Moon0Ravi Hindupur1Iteoluwakishi H. Gamu2Nikki M. McCormack3Fatima Shaikh4James S. Novak5Jyoti K. Jaiswal6Center for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA; Department of Biochemistry and Orthopaedic Surgery, Research Institute of Clinical Medicine of Jeonbuk National University – Biomedical Research Institute of Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea; Institute for Medical Science of Jeonbuk National University Medical School, Jeonju 54896, Republic of KoreaCenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USACenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USACenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USACenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USACenter for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA; Corresponding author: James S. Novak, Center for Genetic Medicine Research, Children’s National Research and Innovation Campus, 7144 13th Pl, NW, Washington, DC 20012, USA.Center for Genetic Medicine Research, Children’s National Research Institute, Children’s National Research and Innovation Campus, Children’s National Hospital, Washington, DC 20012, USA; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC 20052, USA; Corresponding author: Jyoti K. Jaiswal, Center for Genetic Medicine Research, Children’s National Research and Innovation Campus, 7144 13th Pl, NW, Washington, DC 20012, USA.Despite the proven safety of dystrophin-targeting phosphorodiamidate morpholino oligomer (PMO) therapy, poor delivery of the PMOs limit the efficacy of this dystrophin restoring gene therapy for Duchenne muscular dystrophy (DMD). Limited myogenesis and excessive fibrosis in DMD are pathological features that contribute to the poor efficacy of PMOs. We show that the severe DMD mouse model (D2-mdx) not only replicates these pathological features of DMD but also mirrors the resulting PMO-mediated dystrophin restoration deficit. High transforming growth factor β (TGF-β) activity, which is a common feature of DMD patient and D2-mdx muscles, limits myogenesis and causes fibrosis. We developed a TGF-β-targeting PO (TPMO), which when used acutely, lowered macrophage TGF-β activity and signaling in the dystrophic muscle, enhanced muscle regeneration, and enhanced dystrophin restoration when used in combination with dystrophin exon skipping PMO (DPMO). Chronic use of this combination PMO therapy in D2-mdx mice reduced muscle fibrosis and muscle loss, allowed dystrophin restoration in skeletal muscle and heart, and led to an overall enhancement of skeletal muscle function. This approach leverages the safety of PMO-based therapy and represents the first combination PMO treatment for DMD that simultaneously enhances dystrophin restoration, reduces fibrosis, and alleviates myogenic deficits to ultimately improve health and function of dystrophic muscles.http://www.sciencedirect.com/science/article/pii/S2162253125002197MT: Oligonucleotides: Therapies and ApplicationsDuchenne muscular dystrophy, DMDfibrosismyogenesisinflammationfibroadipogenic |
| spellingShingle | Young Jae Moon Ravi Hindupur Iteoluwakishi H. Gamu Nikki M. McCormack Fatima Shaikh James S. Novak Jyoti K. Jaiswal A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications Duchenne muscular dystrophy, DMD fibrosis myogenesis inflammation fibroadipogenic |
| title | A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health |
| title_full | A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health |
| title_fullStr | A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health |
| title_full_unstemmed | A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health |
| title_short | A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health |
| title_sort | combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin deficient muscle health |
| topic | MT: Oligonucleotides: Therapies and Applications Duchenne muscular dystrophy, DMD fibrosis myogenesis inflammation fibroadipogenic |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125002197 |
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