Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse
Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD “exon skipping” uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253118300167 |
| _version_ | 1819139522141618176 |
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| author | Derek W. Wang Ekaterina I. Mokhonova Genevieve C. Kendall Diana Becerra Yalda B. Naeini Rita M. Cantor Melissa J. Spencer Stanley F. Nelson M. Carrie Miceli |
| author_facet | Derek W. Wang Ekaterina I. Mokhonova Genevieve C. Kendall Diana Becerra Yalda B. Naeini Rita M. Cantor Melissa J. Spencer Stanley F. Nelson M. Carrie Miceli |
| author_sort | Derek W. Wang |
| collection | DOAJ |
| description | Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD “exon skipping” uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially functional dystrophin protein. Although exon-skipping drugs in humans show promise, levels of rescued dystrophin protein remain suboptimal. We previously identified dantrolene as a skip booster when combined with AON in human DMD cultures and short-term mdx dystrophic mouse studies. Here, we assess the effect of dantrolene/AON combination on DMD exon-23 skipping over long-term mdx treatment under conditions that better approximate potential human dosing. To evaluate the dantrolene/AON combination treatment effect on dystrophin induction, we assayed three AON doses, with and without oral dantrolene, to assess multiple outcomes across different muscles. Meta-analyses of the results of statistical tests from both the quadriceps and diaphragm assessing contributions of dantrolene beyond AON, across all AON treatment groups, provide strong evidence that dantrolene modestly boosts exon skipping and dystrophin rescue while reducing muscle pathology in mdx mice (p < 0.0087). These findings support a trial of combination dantrolene/AON to increase exon-skipping efficacy and highlight the value of combinatorial approaches and Food and Drug Administration (FDA) drug re-purposing for discovery of unsuspected therapeutic application and rapid translation. |
| first_indexed | 2024-12-22T11:24:00Z |
| format | Article |
| id | doaj.art-a2469c5520d44da1a1bed1d1f93eebcc |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-22T11:24:00Z |
| publishDate | 2018-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-a2469c5520d44da1a1bed1d1f93eebcc2022-12-21T18:27:47ZengElsevierMolecular Therapy: Nucleic Acids2162-25312018-06-0111C18019110.1016/j.omtn.2018.02.002Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx MouseDerek W. Wang0Ekaterina I. Mokhonova1Genevieve C. Kendall2Diana Becerra3Yalda B. Naeini4Rita M. Cantor5Melissa J. Spencer6Stanley F. Nelson7M. Carrie Miceli8Center for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USACenter for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USACenter for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USACenter for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USADepartment of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USADepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USACenter for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USACenter for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USACenter for Duchenne Muscular Dystrophy, University of California, Los Angeles, Los Angeles, CA, USADuchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD “exon skipping” uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially functional dystrophin protein. Although exon-skipping drugs in humans show promise, levels of rescued dystrophin protein remain suboptimal. We previously identified dantrolene as a skip booster when combined with AON in human DMD cultures and short-term mdx dystrophic mouse studies. Here, we assess the effect of dantrolene/AON combination on DMD exon-23 skipping over long-term mdx treatment under conditions that better approximate potential human dosing. To evaluate the dantrolene/AON combination treatment effect on dystrophin induction, we assayed three AON doses, with and without oral dantrolene, to assess multiple outcomes across different muscles. Meta-analyses of the results of statistical tests from both the quadriceps and diaphragm assessing contributions of dantrolene beyond AON, across all AON treatment groups, provide strong evidence that dantrolene modestly boosts exon skipping and dystrophin rescue while reducing muscle pathology in mdx mice (p < 0.0087). These findings support a trial of combination dantrolene/AON to increase exon-skipping efficacy and highlight the value of combinatorial approaches and Food and Drug Administration (FDA) drug re-purposing for discovery of unsuspected therapeutic application and rapid translation.http://www.sciencedirect.com/science/article/pii/S2162253118300167exon skippingDuchenne muscular dystrophydystrophindantrolenecombination therapy |
| spellingShingle | Derek W. Wang Ekaterina I. Mokhonova Genevieve C. Kendall Diana Becerra Yalda B. Naeini Rita M. Cantor Melissa J. Spencer Stanley F. Nelson M. Carrie Miceli Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse Molecular Therapy: Nucleic Acids exon skipping Duchenne muscular dystrophy dystrophin dantrolene combination therapy |
| title | Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse |
| title_full | Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse |
| title_fullStr | Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse |
| title_full_unstemmed | Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse |
| title_short | Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse |
| title_sort | repurposing dantrolene for long term combination therapy to potentiate antisense mediated dmd exon skipping in the mdx mouse |
| topic | exon skipping Duchenne muscular dystrophy dystrophin dantrolene combination therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2162253118300167 |
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