Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping
Duchenne muscular dystrophy (DMD) is an X-linked progressive disease characterized by loss of dystrophin protein that typically results from truncating mutations in the DMD gene. Current exon-skipping therapies have sought to treat deletion mutations that abolish an open reading frame (ORF) by skipp...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050121000541 |
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| author | Tabatha R. Simmons Tatyana A. Vetter Nianyuan Huang Adeline Vulin-Chaffiol Nicolas Wein Kevin M. Flanigan |
| author_facet | Tabatha R. Simmons Tatyana A. Vetter Nianyuan Huang Adeline Vulin-Chaffiol Nicolas Wein Kevin M. Flanigan |
| author_sort | Tabatha R. Simmons |
| collection | DOAJ |
| description | Duchenne muscular dystrophy (DMD) is an X-linked progressive disease characterized by loss of dystrophin protein that typically results from truncating mutations in the DMD gene. Current exon-skipping therapies have sought to treat deletion mutations that abolish an open reading frame (ORF) by skipping an adjacent exon, in order to restore an ORF that allows translation of an internally deleted yet partially functional protein, as is seen with many patients with the milder Becker muscular dystrophy (BMD) phenotype. In contrast to that approach, skipping of one copy of a duplicated exon would be expected to result in a full-length transcript and production of a wild-type protein. We have developed an adeno-associated virus (AAV)-based U7snRNA exon-skipping approach directed toward exon 2, duplications of which represent 10% of all DMD duplication mutations. Deletion of exon 2 results in utilization of an exon 5 internal ribosome entry site (IRES) that allows translation beginning in exon 6 of a highly protective dystrophin protein, providing a wide therapeutic window for treatment. Both intramuscular and systemic administration of this vector in the Dup2 mouse model results in robust dystrophin expression and correction of muscle physiologic defects, allowing dose escalation to establish a putative minimal efficacious dose for a human clinical trial. |
| first_indexed | 2024-12-22T01:53:38Z |
| format | Article |
| id | doaj.art-6912488c4ecd404facb01ca8c3e269ec |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-22T01:53:38Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-6912488c4ecd404facb01ca8c3e269ec2022-12-21T18:42:51ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-06-0121325340Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skippingTabatha R. Simmons0Tatyana A. Vetter1Nianyuan Huang2Adeline Vulin-Chaffiol3Nicolas Wein4Kevin M. Flanigan5Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pediatrics, Ohio State University, Columbus, OH, USACenter for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pediatrics, Ohio State University, Columbus, OH, USA; Corresponding author: Kevin M. Flanigan, MD, Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Rm 3011, 700 Children’s Drive, Columbus, OH 43205, USA.Duchenne muscular dystrophy (DMD) is an X-linked progressive disease characterized by loss of dystrophin protein that typically results from truncating mutations in the DMD gene. Current exon-skipping therapies have sought to treat deletion mutations that abolish an open reading frame (ORF) by skipping an adjacent exon, in order to restore an ORF that allows translation of an internally deleted yet partially functional protein, as is seen with many patients with the milder Becker muscular dystrophy (BMD) phenotype. In contrast to that approach, skipping of one copy of a duplicated exon would be expected to result in a full-length transcript and production of a wild-type protein. We have developed an adeno-associated virus (AAV)-based U7snRNA exon-skipping approach directed toward exon 2, duplications of which represent 10% of all DMD duplication mutations. Deletion of exon 2 results in utilization of an exon 5 internal ribosome entry site (IRES) that allows translation beginning in exon 6 of a highly protective dystrophin protein, providing a wide therapeutic window for treatment. Both intramuscular and systemic administration of this vector in the Dup2 mouse model results in robust dystrophin expression and correction of muscle physiologic defects, allowing dose escalation to establish a putative minimal efficacious dose for a human clinical trial.http://www.sciencedirect.com/science/article/pii/S2329050121000541Duchenne muscular dystrophyBecker muscular dystrophydystrophinexon skippingU7snRNAgene therapy |
| spellingShingle | Tabatha R. Simmons Tatyana A. Vetter Nianyuan Huang Adeline Vulin-Chaffiol Nicolas Wein Kevin M. Flanigan Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping Molecular Therapy: Methods & Clinical Development Duchenne muscular dystrophy Becker muscular dystrophy dystrophin exon skipping U7snRNA gene therapy |
| title | Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping |
| title_full | Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping |
| title_fullStr | Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping |
| title_full_unstemmed | Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping |
| title_short | Pre-clinical dose-escalation studies establish a therapeutic range for U7snRNA-mediated DMD exon 2 skipping |
| title_sort | pre clinical dose escalation studies establish a therapeutic range for u7snrna mediated dmd exon 2 skipping |
| topic | Duchenne muscular dystrophy Becker muscular dystrophy dystrophin exon skipping U7snRNA gene therapy |
| url | http://www.sciencedirect.com/science/article/pii/S2329050121000541 |
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